Novel phosphonic acid compounds as inhibitors of serine proteases

ABSTRACT

The present invention is directed to phosphonic acid compounds useful as serine protease inhibitors, compositions thereof and methods for treating inflammatory and serine protease mediated disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 10/414,782, filed Apr.16, 2003, which is a continuation-in-part of U.S. Ser. No. 10/273,208,filed Oct. 17, 2002, now abandoned, which claims benefit of provisionalapplication Ser. No. 60/330,343, filed Oct. 19, 2001, which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to certain novel compounds, methods forpreparing the compounds, compositions, intermediates and derivativesthereof and for treating inflammatory and serine protease mediateddisorders. More particularly, the phosphonic acid compounds of thepresent invention are serine protease inhibitors useful for treatinginflammatory and serine protease mediated disorders.

BACKGROUND OF THE INVENTION

Serine proteases represent a broad class of endopeptidases that areinvolved in physiological processes such as blood coagulation,complement activation, phagocytosis and turnover of damaged cell tissue.For example, cathepsin G (cat G) is a chymotrypsin-like serine proteasefound in the azurophilic granules of polymorphonuclear leukocytes. Alongwith other serine proteases such as human neutrophil elastase andprotease 3, cat G functions to degrade proteins during inflammatoryresponses. Cat G is thought to degrade human elastin during chronic lunginflammation, a process which may in part be responsible for asthma,pulmonary emphysema, chronic obstructive pulmonary diseases (COPD) aswell as other pulmonary inflammatory conditions. Similarly, humanchymase (HC) is a chymotrypsin-like serine protease synthesized in mastcells. HC has a variety of functions, including degradation ofextracellular matrix proteins, cleavage of angiotensin I to angiotensinII and activation of matrix proteases and cytokines. Inadequate controlby their natural inhibitors can cause these enzymes to degrade healthyconstituents of the extracellular matrix, and thereby contribute toinflammatory disorders such as asthma, emphysema, bronchitis, psoriasis,allergic rhinitis, viral rhinitis, ischemia, arthritis and reperfusioninjury. Thus, small molecule inhibitors of cat G and HC are likely torepresent useful therapeutic agents.

U.S. Pat. No. 5,508,273 to Beers, et al. and Bioorganic & Med. Chem.Lett., 1995, 5, (16), 1801-1806 describe phosphonic acid compoundsuseful in treating bone wasting diseases. In particular,1-napthylmethylphosphonic acid derivatives have been described asosteoclastic acid phosphatase inhibitors of the formula:

Accordingly, it is an object of the present invention to providephosphonic acid compounds that are serine protease inhibitors (inparticular, inhibitors of cathepsin G and chymase) useful for treatinginflammatory and serine protease mediated disorders. It is anotherobject of the invention to provide a process for preparing phosphonic orphosphinic acid compounds, compositions, intermediates and derivativesthereof. It is a further object of the invention to provide methods fortreating inflammatory and serine protease mediated disorders.

SUMMARY OF THE INVENTION

This invention is directed to compounds of Formula (I):

wherein

-   R₁ is selected from the group consisting of a heterocyclyl ring    (wherein the point of attachment for the heterocyclyl ring at R₁ is    a nitrogen ring atom) and —N(R₇R₈); wherein the heterocyclyl ring is    optionally substituted with one to two substituents independently    selected from the group consisting of:-   a). C₁₋₈ alkyl optionally substituted on a terminal carbon atom with    a substituent selected from the group consisting of aryl,    heteroaryl, (halo)₁₋₃ and hydroxy;-   b). C₁₋₈ alkoxy optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of carboxyl,    (halo)₁₋₃ and hydroxy;-   c). aryl;-   d). heteroaryl;-   e). cyano;-   f). halogen;-   g). hydroxy;-   h). nitro; and,-   i). heterocyclyl optionally substituted with one to two substituents    independently selected from the group consisting of oxo and aryl;    and, optionally fused with the carbon of attachment to form a spiro    heterocyclyl moiety;-   and, wherein the aryl portion of the a). and i). substituent, the    heteroaryl portion of the a). substituent and the c). aryl and d).    heteroaryl substituents are optionally substituted with one to four    substituents independently selected from the group consisting of    C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, cycloalkyl, heterocyclyl,    aryl, aryl(C₁₋₄)alkyl, aryloxy, heteroaryl, heteroaryl(C₁₋₄)alkyl,    halogen, hydroxy, nitro, (halo)₁₋₃(C₁₋₄)alkyl and    (halo)₁₋₃(C₁₋₄)alkoxy;-   R₇ is selected from the group consisting of hydrogen, C₁₋₈ alkyl and    C₂₋₈ alkenyl;-   R₈ is selected from the group consisting of:-   aa). C₁₋₈ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of cycloalkyl,    heterocyclyl, aryl, heteroaryl, amino (with two substituents    independently selected from the group consisting of hydrogen and    C₁₋₈ alkyl), (halo)₁₋₃ and hydroxy;-   ab). cycloalkyl;-   ac). cycloalkenyl; and,-   ad). heterocyclyl (wherein the point of attachment at R₈ is a carbon    ring atom);-   wherein the ab). cycloalkyl, ac). cycloalkenyl and ad). heterocyclyl    (wherein the ad). heterocyclyl contains at least one nitrogen ring    atom) substituents and the cycloalkyl, heterocyclyl, aryl and    heteroaryl portions of the aa). substituent are optionally    substituted with one to four substituents independently selected    from the group consisting of:-   ba). C₁₋₈ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of amino (with    two substituents independently selected from the group consisting of    hydrogen and C₁₋₈ alkyl), (halo)₁₋₃ and hydroxy;-   bb). C₁₋₈ alkoxy optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of carboxyl,    (halo)₁₋₃ and hydroxy;-   bc). carbonyl substituted with a substituent selected from the group    consisting of C₁₋₈ alkyl, aryl, aryl(C₁₋₈)alkyl, aryl(C₂₋₈)alkenyl,    heteroaryl, heteroaryl(C₁₋₈)alkyl and heteroaryl(C₂₋₈)alkenyl;-   bd). aryl;-   be). heteroaryl;-   bf). amino substituted with two substituents independently selected    from the group consisting of hydrogen and C₁₋₈ alkyl;-   bg). cyano;-   bh). halogen;-   bi). hydroxy;-   bj). nitro;-   bk). heterocyclyl optionally substituted with one to two oxo    substituents; and,-   bl). sulfonyl substituted with a substituent selected from the group    consisting of C₁₋₈ alkyl, aryl, aryl(C₁₋₈)alkyl, aryl(C₂₋₈)alkenyl,    heteroaryl, heteroaryl(C₁₋₈)alkyl and heteroaryl(C₂₋₈)alkenyl;-   wherein the bd). aryl, be). heteroaryl and bk). heterocyclyl    substituents and the aryl and heteroaryl portions of the bc).    substituent are optionally substituted with one to four substituents    independently selected from the group consisting of C₁₋₄ alkyl    (optionally substituted on a terminal carbon atom with a substituent    selected from the group consisting of amino (substituted with two    substituents independently selected from the group consisting of    hydrogen and C₁₋₈ alkyl), (halo)₁₋₃ and hydroxy), C₁₋₄ alkoxy    (optionally substituted on a terminal carbon atom with a substituent    selected from the group consisting of (halo)₁₋₃), amino (substituted    with two substituents independently selected from the group    consisting of hydrogen and C₁₋₄ alkyl), halogen, hydroxy and nitro;-   and, provided that the optional substituent attached to the ad).    heterocyclyl nitrogen ring atom is not selected from the group    consisting of bf). amino (substituted with two substituents    independently selected from the group consisting of hydrogen and    C₁₋₈ alkyl), bh). halogen, bi). hydroxy and bj). nitro;-   R₄ is selected from the group consisting of C₁₋₄ alkyl (optionally    substituted on a terminal carbon atom with a substituent selected    from the group consisting of aryl and heteroaryl), aryl and    heteroaryl; wherein aryl and heteroaryl and the aryl and heteroaryl    portions of the substituted alkyl are optionally substituted with    one to four substituents independently selected from the group    consisting of C₁₋₄ alkyl, amino (substituted with two substituents    independently selected from the group consisting of hydrogen and    C₁₋₄ alkyl), cyano, halogen, hydroxy and (halo)₁₋₃(C₁₋₈)alkyl;-   R₂ and R₃ are attached to a benzene ring and independently selected    from the group consisting of-   ca). hydrogen;-   cb). C₁₋₄ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of amino    (substituted with two substituents independently selected from the    group consisting of hydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy;-   cc). C₁₋₄ alkoxy optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of (halo)₁₋₃    and hydroxy;-   cd). C₂₋₄ alkenyl;-   ce). amino substituted with two substituents independently selected    from the group consisting of hydrogen and C₁₋₄ alkyl;-   cf). halogen; and,-   cg). hydroxy;-   optionally, R₂ and R₃ together form at least one ring fused to the    benzene ring; thereby providing a multiple ring system; wherein the    multiple ring system is selected from the group consisting of C₉-C₁₄    benzo fused cycloalkyl, C₉-C₁₄ benzo fused cycloalkenyl, C₉-C₁₄    benzo fused aryl, benzo fused heterocyclyl and benzo fused    heteroaryl; and, wherein the multiple ring system can optionally be    substituted with one to four substituents independently selected    from the group consisting of-   da). C₁₋₄ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of amino    (substituted with two substituents independently selected from the    group consisting of hydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy;-   db). C₁₋₄ alkoxy optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of (halo)₁₋₃    and hydroxy;-   dc). amino substituted with two substituents independently selected    from the group consisting of hydrogen and C₁₋₄ alkyl;-   dd). halogen;-   de). hydroxy; and,-   df). nitro;-   R₅ is selected from the group consisting of hydrogen and C₁₋₈ alkyl    (optionally substituted on a terminal carbon atom with a substituent    selected from the group consisting of amino (substituted with two    substituents independently selected from the group consisting of    hydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy) and aryl    (optionally substituted with one to four substituents independently    selected from the group consisting of C₁₋₈ alkyl and halogen);-   R₆ is selected from the group consisting of C₁₋₈ alkyl,    aryl(C₁₋₈)alkyl, C₁₋₈ alkoxy, aryl(C₁₋₈)alkoxy, C₂₋₈ alkenyl, C₂₋₈    alkenyloxy, aryl(C₂₋₈)alkenyl, aryl(C₂₋₈)alkenyloxy, aryl, aryloxy    and hydroxy;-   X and Y are independently selected from the group consisting of    hydrogen, C₁₋₈ alkyl (optionally substituted on a terminal carbon    atom with a substituent selected from the group consisting of    cycloalkyl, heterocyclyl, aryl, heteroaryl, amino (substituted with    two substituents independently selected from the group consisting of    hydrogen and C₁₋₈ alkyl), (halo)₁₋₃ and hydroxy), C₁₋₈ alkoxy    (optionally substituted on a terminal carbon atom with a substituent    selected from the group consisting of aryl, (halo)₁₋₃ and hydroxy),    C₂₋₈ alkenyloxy, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl    and hydroxy; optionally, X and Y are fused together with the carbon    of attachment to form a spiro cycloalkyl or heterocyclyl moiety;    and, optionally, Y is not present; wherein X is one substituent    attached by a double-bond selected from the group consisting of O,    S, imino, (C₁₋₄)alkylimino and hydroxyimino; and,-   Z is selected from the group consisting of a bond, hydrogen and C₁₋₈    alkyl; if Z is a bond (wherein Z forms a double bond with the carbon    of attachment for X), then Y is not present and X is one substituent    attached by a single-bond selected from the group consisting of    hydrogen, C₁₋₈ alkoxy, C₂₋₈ alkenyloxy, aryloxy, aryl(C₁₋₄)alkoxy    and hydroxy,    and isomers, racemates, enantiomers, diastereomers and salts    thereof.

Embodiments of the present invention include a process for preparing acompound of Formula (I) comprising coupling under suitable conditions afirst compound of Formula (A):

-   with a second compound selected from the group consisting of    Formula (B) and Formula (C):

-   to produce a third compound selected from the group consisting of    Formula (D) and Formula (E):

wherein

-   R₇ is selected from the group consisting of hydrogen, C₁₋₈ alkyl and    C₂₋₈ alkenyl;-   R₈ is selected from the group consisting of:-   aa). C₁₋₈ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of cycloalkyl,    heterocyclyl, aryl, heteroaryl, amino (substituted with two    substituents independently selected from the group consisting of    hydrogen and C₁₋₈ alkyl), (halo)₁₋₃ and hydroxy;-   ab). cycloalkyl;-   ac). cycloalkenyl; and,-   ad). heterocyclyl (wherein the point of attachment at R₈ is a carbon    ring atom);-   wherein the ab). cycloalkyl, ac). cycloalkenyl and ad). heterocyclyl    (wherein the ad). heterocyclyl contains at least one nitrogen ring    atom) substituents and the cycloalkyl, heterocyclyl, aryl and    heteroaryl portions of the aa). substituent are optionally    substituted with one to four substituents independently selected    from the group consisting of:-   ba). C₁₋₈ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of amino (with    two substituents independently selected from the group consisting of    hydrogen and C₁₋₈ alkyl), (halo)₁₋₃ and hydroxy;-   bb). C₁₋₈ alkoxy optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of carboxyl,    (halo)₁₋₃ and hydroxy;-   bc). carbonyl substituted with a substituent selected from the group    consisting of C₁₋₈ alkyl, aryl, aryl(C₁₋₈)alkyl, aryl(C₂₋₈)alkenyl,    heteroaryl, heteroaryl(C₁₋₈)alkyl and heteroaryl(C₂₋₈)alkenyl;-   bd). aryl;-   be). heteroaryl;-   bf). amino substituted with two substituents independently selected    from the group consisting of hydrogen and C₁₋₈ alkyl;-   bg). cyano;-   bh). halogen;-   bi). hydroxy;-   bj). nitro;-   bk). heterocyclyl optionally substituted with one to two oxo    substituents; and,-   bl). sulfonyl substituted with a substituent selected from the group    consisting of C₁₋₈ alkyl, aryl, aryl(C₁₋₈)alkyl, aryl(C₂₋₈)alkenyl,    heteroaryl, heteroaryl(C₁₋₈)alkyl and heteroaryl(C₂₋₈)alkenyl;-   wherein the bd). aryl, be). heteroaryl and bk). heterocyclyl    substituents and the aryl and heteroaryl portions of the bc).    substituent are optionally substituted with one to four substituents    independently selected from the group consisting of C₁₋₄ alkyl    (optionally substituted on a terminal carbon atom with a substituent    selected from the group consisting of amino (substituted with two    substituents independently selected from the group consisting of    hydrogen and C₁₋₈ alkyl), (halo)₁₋₃ and hydroxy), C₁₋₄ alkoxy    (optionally substituted on a terminal carbon atom with a substituent    selected from the group consisting of (halo)₁₋₃), amino (substituted    with two substituents independently selected from the group    consisting of hydrogen and C₁₋₄ alkyl), halogen, hydroxy and nitro;-   and, provided that the optional substituent attached to the ad).    heterocyclyl nitrogen ring atom is not selected from the group    consisting of bf). amino (substituted with two substituents    independently selected from the group consisting of hydrogen and    C₁₋₈ alkyl), bh). halogen, bi). hydroxy and bj). nitro;-   R₄ is selected from the group consisting of C₁₋₄ alkyl (optionally    substituted on a terminal carbon atom with a substituent selected    from the group consisting of aryl and heteroaryl), aryl and    heteroaryl; wherein aryl and heteroaryl and the aryl and heteroaryl    portions of the substituted alkyl are optionally substituted with    one to four substituents independently selected from the group    consisting of C₁₋₄ alkyl, amino (substituted with two substituents    independently selected from the group consisting of hydrogen and    C₁₋₄ alkyl), cyano, halogen, hydroxy and (halo)₁₋₃(C₁₋₈)alkyl;-   R₂ and R₃ are attached to a benzene ring and independently selected    from the group consisting of-   ca). hydrogen;-   cb). C₁₋₄ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of amino    (substituted with two substituents independently selected from the    group consisting of hydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy;-   cc). C₁₋₄ alkoxy optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of (halo)₁₋₃    and hydroxy;-   cd). C₂₋₄ alkenyl;-   ce). amino substituted with two substituents independently selected    from the group consisting of hydrogen and C₁₋₄ alkyl;-   cf. halogen; and,-   cg). hydroxy;-   optionally, R₂ and R₃ together form at least one ring fused to the    benzene ring; thereby providing a multiple ring system; wherein the    multiple ring system is selected from the group consisting of C₉-C₁₄    benzo fused cycloalkyl, C₉-C₁₄ benzo fused cycloalkenyl, C₉-C₁₄    benzo fused aryl, benzo fused heterocyclyl and benzo fused    heteroaryl; and, wherein the multiple ring system can optionally be    substituted with one to four substituents independently selected    from the group consisting of:-   da). C₁₋₄ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of amino    (substituted with two substituents independently selected from the    group consisting of hydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy;-   db). C₁₋₄ alkoxy optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of (halo)₁₋₃    and hydroxy;-   dc). amino substituted with two substituents independently selected    from the group consisting of hydrogen and C₁₋₄ alkyl;-   dd). halogen;-   de). hydroxy; and,-   df). nitro;-   R₅ is selected from the group consisting of hydrogen and C₁₋₈ alkyl    (optionally substituted on a terminal carbon atom with a substituent    selected from the group consisting of amino (substituted with two    substituents independently selected from the group consisting of    hydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy) and aryl    (optionally substituted with one to four substituents independently    selected from the group consisting of C₁₋₈ alkyl and halogen);-   R₆ is selected from the group consisting of C₁₋₈ alkyl,    aryl(C₁₋₈)alkyl, C₁₋₈ alkoxy, aryl(C₁₋₈)alkoxy, C₂₋₈ alkenyl, C₂₋₈    alkenyloxy, aryl(C₂₋₈)alkenyl, aryl(C₂₋₈)alkenyloxy, aryl, aryloxy    and hydroxy;-   X is selected from the group consisting of O, S, imino,    (C₁₋₄)alkylimino and hydroxyimino; and,-   Z is selected from the group consisting of a bond, hydrogen and C₁₋₈    alkyl; if Z is a bond (wherein Z forms a double bond with the carbon    of attachment for X), then X is selected from the group consisting    of hydrogen, C₁₋₈ alkoxy, C₂₋₈ alkenyloxy, aryloxy, aryl(C₁₋₄)alkoxy    and hydroxy,    and isomers, racemates, enantiomers, diastereomers and salts    thereof.

Embodiments of the present invention include a compound of Formula (C):

wherein

-   R₂ and R₃ are attached to a benzene ring and independently selected    from the group consisting of-   ca). hydrogen;-   cb). C₁₋₄ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of amino    (substituted with two substituents independently selected from the    group consisting of hydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy;-   cc). C₁₋₄ alkoxy optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of (halo)₁₋₃    and hydroxy;-   cd). C₂₋₄ alkenyl;-   ce). amino substituted with two substituents independently selected    from the group consisting of hydrogen and C₁₋₄ alkyl;-   cf). halogen; and,-   cg). hydroxy;-   optionally, R₂ and R₃ together form at least one ring fused to the    benzene ring; thereby providing a multiple ring system; wherein the    multiple ring system is selected from the group consisting of C₉-C₁₄    benzo fused cycloalkyl, C₉-C₁₄ benzo fused cycloalkenyl, C₉-C₁₄    benzo fused aryl, benzo fused heterocyclyl and benzo fused    heteroaryl; and, wherein the multiple ring system can optionally be    substituted with one to four substituents independently selected    from the group consisting of-   da). C₁₋₄ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of amino    (substituted with two substituents independently selected from the    group consisting of hydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy;-   db). C₁₋₄ alkoxy optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of (halo)₁₋₃    and hydroxy;-   dc). amino substituted with two substituents independently selected    from the group consisting of hydrogen and C₁₋₄ alkyl;-   dd). halogen;-   de). hydroxy; and,-   df). nitro;-   R₄ is selected from the group consisting of C₁₋₄ alkyl (optionally    substituted on a terminal carbon atom with a substituent selected    from the group consisting of aryl and heteroaryl), aryl and    heteroaryl; wherein aryl and heteroaryl and the aryl and heteroaryl    portions of the substituted alkyl are optionally substituted with    one to four substituents independently selected from the group    consisting of C₁₋₄ alkyl, amino (substituted with two substituents    independently selected from the group consisting of hydrogen and    C₁₋₄ alkyl), cyano, halogen, hydroxy and (halo)₁₋₃(C₁₋₈)alkyl;-   R₅ is selected from the group consisting of hydrogen and C₁₋₈ alkyl    (optionally substituted on a terminal carbon atom with a substituent    selected from the group consisting of amino (substituted with two    substituents independently selected from the group consisting of    hydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy) and aryl    (optionally substituted with one to four substituents independently    selected from the group consisting of C₁₋₈ alkyl and halogen); and,-   R₆ is selected from the group consisting of C₁₋₈ alkyl,    aryl(C₁₋₈)alkyl, C₁₋₈ alkoxy, aryl(C₁₋₈)alkoxy, C₂₋₈ alkenyl, C₂₋₈    alkenyloxy, aryl(C₂₋₈)alkenyl, aryl(C₂₋₈)alkenyloxy, aryl, aryloxy    and hydroxy.

Embodiments of the present invention include a process for making abenzolactone of Formula (C) comprising

-   a) reacting an anhydride of Formula (F):

with a compound of Formula (G):

under suitable conditions in the presence of an alkali metal (M) toprovide a compound of Formula (H):

-   b) and, reacting the compound of Formula (H) under conditions    suitable to form the benzolactone of Formula (C):

wherein

-   R₂ and R₃ are attached to a benzene ring and independently selected    from the group consisting of-   ca). hydrogen;-   cb). C₁₋₄ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of amino    (substituted with two substituents independently selected from the    group consisting of hydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy;-   cc). C₁₋₄ alkoxy optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of (halo)₁₋₃    and hydroxy;-   cd). C₂₋₄ alkenyl;-   ce). amino substituted with two substituents independently selected    from the group consisting of hydrogen and C₁₋₄ alkyl;-   cf. halogen; and,-   cg). hydroxy;-   optionally, R₂ and R₃ together form at least one ring fused to the    benzene ring; thereby providing a multiple ring system; wherein the    multiple ring system is selected from the group consisting of C₉-C₁₄    benzo fused cycloalkyl, C₉-C₁₄ benzo fused cycloalkenyl, C₉-C₁₄    benzo fused aryl, benzo fused heterocyclyl and benzo fused    heteroaryl; and, wherein the multiple ring system can optionally be    substituted with one to four substituents independently selected    from the group consisting of-   da). C₁₋₄ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of amino    (substituted with two substituents independently selected from the    group consisting of hydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy;-   db). C₁₋₄ alkoxy optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of (halo)₁₋₃    and hydroxy;-   dc). amino substituted with two substituents independently selected    from the group consisting of hydrogen and C₁₋₄ alkyl;-   dd). halogen;-   de). hydroxy; and,-   df. nitro;-   R₄ is selected from the group consisting of C₁₋₄ alkyl (optionally    substituted on a terminal carbon atom with a substituent selected    from the group consisting of aryl and heteroaryl), aryl and    heteroaryl; wherein aryl and heteroaryl and the aryl and heteroaryl    portions of the substituted alkyl are optionally substituted with    one to four substituents independently selected from the group    consisting of C₁₋₄ alkyl, amino (substituted with two substituents    independently selected from the group consisting of hydrogen and    C₁₋₄ alkyl), cyano, halogen, hydroxy and (halo)₁₋₃(C₁₋₈)alkyl;-   R₅ is selected from the group consisting of hydrogen and C₁₋₈ alkyl    (optionally substituted on a terminal carbon atom with a substituent    selected from the group consisting of amino (substituted with two    substituents independently selected from the group consisting of    hydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy) and aryl    (optionally substituted with one to four substituents independently    selected from the group consisting of C₁₋₈ alkyl and halogen); and-   R₆ is selected from the group consisting of C₁₋₈ alkyl,    aryl(C₁₋₈)alkyl, C₁₋₈ alkoxy, aryl(C₁₋₈)alkoxy, C₂₋₈ alkenyl, C₂₋₈    alkenyloxy, aryl(C₂₋₈)alkenyl, aryl(C₂₋₈)alkenyloxy, aryl, aryloxy    and hydroxy.

Embodiments of the present invention include compounds of Formula (II):

wherein

-   R₁₀ is selected from the group consisting of:-   a). sulfonyl substituted with a substituent selected from the group    consisting of C₁₋₈ alkyl, aryl, aryl(C₁₋₈)alkyl, aryl(C₂₋₈)alkenyl,    cycloalkyl, cycloalkenyl, heterocycyl, heteroaryl,    heteroaryl(C₁₋₈)alkyl and heteroaryl(C₂₋₈)alkenyl;-   b). carbonyl substituted with a substituent selected from the group    consisting of C₁₋₈ alkyl, aryl, aryl(C₁₋₈)alkyl, aryl(C₂₋₈)alkenyl,    cycloalkyl, cycloalkenyl, heterocycyl heteroaryl,    heteroaryl(C₁₋₈)alkyl, heteroaryl(C₂₋₈)alkenyl, —OR₁₁, and amino    (with two substituents independently selected from the group    consisting of hydrogen, C₁₋₈ alkyl, aryl, arylC₁₋₈ alkyl,    arylcarbonyl, arylC₁₋₈ alkyl carbonyl and heteroaryl C₁₋₈ alkyl);-   c). C₁₋₈ alkyl optionally substituted on a terminal carbon atom with    a substituent selected from the group consisting of aryl,    cycloalkyl, cycloalkenyl, heterocycl, heteroaryl, (halo)₁₋₃,    hydroxy, —C(O)R₁₂ and amino (with two substituents independently    selected from the group consisting of hydrogen, C₁₋₈ alkyl, arylC₁₋₈    alkyl, arylcarbonyl, arylC₁₋₈ alkyl carbonyl and heteroaryl C₁₋₈    alkyl);-   d). aryl;-   e). heteroaryl;-   f). cycloalkyl-   g). cycloalkenyl; and,-   h). heterocyclyl-   wherein the heterocycyl, cycloalkyl, cycloalkenyl portion of a).,    b)., and c)., the cylcoalkyl f)., cylcoalkenyl g)., and heterocyclyl    h). are optionally substituted with one to two substituents    independently selected from the group consisting of:    -   ea). oxo    -   eb). carbonyl substituted with a substituent selected from the        group consisting of C₁₋₈ alkyl, aryl, aryl(C₁₋₈)alkyl,        aryl(C₂₋₈)alkenyl, cycloalkyl, cycloalkenyl, heterocycl        heteroaryl, heteroaryl(C₁₋₈)alkyl, heteroaryl(C₂₋₈)alkenyl and        amino (with two substituents independently selected from the        group consisting of hydrogen, C₁₋₈ alkyl, arylC₁₋₈ alkyl,        arylcarbonyl, arylC₁₋₈ alkyl carbonyl and heteroaryl C₁₋₈        alkyl);    -   ec). C₁₋₈ alkyl optionally substituted with a substituent        selected from the group consisting of amino (with two        substituents independently selected from the group consisting of        hydrogen, C₁₋₈ alkyl, arylC₁₋₈ alkyl, arylcarbonyl, arylC₁₋₈        alkyl carbonyl and heteroaryl C₁₋₈ alkyl), aryl, cycloalkyl,        cycloalkenyl, heterocycl, heteroaryl, (halo)₁₋₃, and hydroxy;    -   ed). aryl; and    -   ef. (halo)₁₋₃-   wherein the aryl portion of the a)., b)., c)., ec). and ed).    substituents, the heteroaryl portion of the a)., b)., c). and ec).    substituents and the d). aryl and e). heteroaryl substituents are    optionally substituted with one to four substituents independently    selected from the group consisting of-   fa). C₁₋₄ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of aryl,    cycloalkyl, cycloalkenyl, heterocycl, heteroaryl, (halo)₁₋₃,    hydroxy, —C(O)R₁₂ and amino (with two substituents independently    selected from the group consisting of hydrogen, C₁₋₈ alkyl, arylC₁₋₈    alkyl, arylcarbonyl, arylC₁₋₈ alkyl carbonyl and heteroaryl C₁₋₈    alkyl);-   fb). C₂₋₄ alkenyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of amino (with    two substituents independently selected from the group consisting of    hydrogen and C₁₋₈ alkyl), (halo)₁₋₃ and hydroxy;-   fc). C₁₋₄ alkoxy optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of (halo)₁₋₃    and hydroxy;-   fd). cycloalkyl,-   fe). heterocyclyl,-   ff). aryl optionally substituted with one to four substituents    independently selected from the group consisting of C₁₋₈ alkyl and    halogen;-   fg). heteroaryl,-   fh). hydroxy;-   fi). hydroxy;-   fj). nitro; and-   fk). (halo)₁₋₃;-   wherein the aryl portion of the arylC₁₋₈ alkyl, arylcarbonyl,    arylC₁₋₈ alkyl carbonyl of fa). are optionally substituted with one    to four substituents independently selected from the group    consisting of C₁₋₄ alkyl (optionally substituted on a terminal    carbon atom with a substituent selected from the group consisting of    amino (substituted with two substituents independently selected from    the group consisting of hydrogen and C₁₋₈ alkyl), (halo)₁₋₃ and    hydroxy), C₁₋₄ alkoxy (optionally substituted on a terminal carbon    atom with a substituent selected from the group consisting of    (halo)₁₋₃), amino (substituted with two substituents independently    selected from the group consisting of hydrogen and C₁₋₄ alkyl),    halogen, hydroxy and nitro.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the percent change in specific lung resistance (SR_(L))from baseline for Compound 2 compared to control in a spontaneousascaris suum antigen-induced model of asthma in sheep over an 8 hourperiod.

FIG. 2 shows the change in the cumulative carbachol dose required toincrease SR_(L) 400% (PC 400) from a baseline value (BSL) measured at 24hours post-dosing of Compound 2 in the spontaneous ascaris suumantigen-induced model of asthma in sheep compared to a 24 hourpost-dosing challenge with carbachol (Post Antigen).

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention include those compounds wherein R₁is selected from the group consisting of a heterocyclyl ring (whereinthe point of attachment for the heterocyclyl ring at R₁ is a nitrogenring atom) and —N(R₇R₈); wherein the heterocyclyl ring is optionallysubstituted with a substituent selected from the group consisting of a).aryl(C₁₋₄)alkyl, c). aryl, d). heteroaryl and i). heterocyclyl(optionally substituted with one to two substituents independentlyselected from the group consisting of oxo and aryl; and, optionallyfused with the carbon of attachment to form a spiro heterocyclylmoiety); and, wherein the aryl portion of the a). and i). substituentand the c). aryl substituent are optionally substituted with one to twosubstituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ alkoxy, aryl, heteroaryl, halogen, hydroxy,(halo)₁₋₃(C₁₋₄)alkyl and (halo)₁₋₃(C₁₋₄)alkoxy; and, all other variablesare as previously defined.

Preferably, R₁ is selected from the group consisting of a heterocyclylring (wherein the point of attachment for the heterocyclyl ring at R₁ isa nitrogen ring atom) and —N(R₇R₈); wherein the heterocyclyl ring isoptionally substituted with a substituent selected from the groupconsisting of a). aryl(C₁₋₄)alkyl, c). aryl, d). heteroaryl and i).heterocyclyl (optionally substituted with two substituents independentlyselected from the group consisting of oxo and aryl; and, optionallyfused with the carbon of attachment to form a spiro heterocyclylmoiety); and, wherein the aryl portion of the a). and i). substituentand the c). aryl substituent are optionally substituted with one to twosubstituents independently selected from the group consisting of C₁₋₄alkoxy and aryl; and, all other variables are as previously defined.

More preferably, R₁ is selected from the group consisting ofpyrrolidinyl, piperidinyl and —N(R₇R₈); wherein the point of attachmentfor pyrrolidinyl and piperidinyl is a nitrogen ring atom; and, whereinpyrrolidinyl and piperidinyl are optionally substituted with asubstituent selected from the group consisting of a). phenylethyl, c).phenyl (optionally substituted with methoxy), d). benzothiazolyl and i).imidazolidinyl (optionally substituted with two substituentsindependently selected from the group consisting of oxo and phenyl; and,optionally fused with the carbon of attachment to form a spiro moiety);and, all other variables are as previously defined.

Most preferably, R₁ is selected from the group consisting ofpyrrolidinyl, piperidinyl and —N(R₇R₈); wherein the point of attachmentfor pyrrolidinyl and piperidinyl is a nitrogen ring atom in the oneposition; and, wherein pyrrolidinyl and piperidinyl are optionallysubstituted with a substituent selected from the group consisting of a).phenylethyl, c). phenyl (optionally substituted with methoxy), d).benzothiazolyl and i). imidazolidinyl (optionally substituted with twosubstituents independently selected from the group consisting of oxo andphenyl; and, optionally fused with the carbon of attachment to form aspiro moiety); and, all other variables are as previously defined.

Preferred embodiments of the present invention include those compoundswherein R₇ is selected from the group consisting of hydrogen, C₁₋₄ alkyland C₂₋₄ alkenyl.

More preferably, R₇ is selected from the group consisting of hydrogenand C₁₋₄ alkyl.

Most preferably, R₇ is selected from the group consisting of hydrogenand methyl.

Embodiments of the present invention include those compounds wherein R₈is selected from the group consisting of:

-   aa). C₁₋₈ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of cycloalkyl,    heterocyclyl, (halo)₁₋₃ and hydroxy;-   ab). cycloalkyl;-   ac). cycloalkenyl; and,-   ad). heterocyclyl (wherein the point of attachment at R₈ is a carbon    ring atom); wherein the ab). cycloalkyl, ac). cycloalkenyl and ad).    heterocyclyl substituents (wherein the ad). heterocyclyl contains at    least one nitrogen ring atom) and the cycloalkyl portion of the aa).    substituent are optionally substituted with one to four substituents    independently selected from the group consisting of:-   ba). C₁₋₈ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of amino (with    two substituents independently selected from the group consisting of    hydrogen and C₁₋₈ alkyl), (halo)₁₋₃ and hydroxy;-   bb). C₁₋₈ alkoxy;-   bc). carbonyl substituted with a substituent selected from the group    consisting of C₁₋₈ alkyl, aryl, aryl(C₁₋₈)alkyl, aryl(C₂₋₈)alkenyl,    heteroaryl, heteroaryl(C₁₋₈)alkyl and heteroaryl(C₂₋₈)alkenyl;-   bd). aryl;-   be). heteroaryl;-   bf). amino substituted with two substituents independently selected    from the group consisting of hydrogen and C₁₋₈ alkyl;-   bh). halogen;-   bi). hydroxy;-   bk). heterocyclyl; and,-   bl). sulfonyl substituted with a substituent selected from the group    consisting of C₁₋₈ alkyl, aryl, aryl(C₁₋₈)alkyl, aryl(C₂₋₈)alkenyl,    heteroaryl, heteroaryl(C₁₋₈)alkyl and heteroaryl(C₂₋₈)alkenyl;-   wherein the bd). aryl, be). heteroaryl and bk). heterocyclyl    substituents and the aryl and heteroaryl portions of the bc).    substituent are optionally substituted with one to four substituents    independently selected from the group consisting of C₁₋₄ alkyl    (optionally substituted on a terminal carbon atom with a substituent    selected from the group consisting of (halo)₁₋₃), C₁₋₄ alkoxy, amino    (substituted with two substituents independently selected from the    group consisting of hydrogen and C₁₋₄ alkyl), halogen and hydroxy;-   and, provided that the optional substituent attached to the ad).    heterocyclyl nitrogen ring atom is not selected from the group    consisting of bf). amino (substituted with two substituents    independently selected from the group consisting of hydrogen and    C₁₋₈ alkyl), bh). halogen, bi). hydroxy and bj). nitro.

Preferably, R₈ is selected from the group consisting of aa).cycloalkyl(C₁₋₄)alkyl, ab). cycloalkyl, ac). cycloalkenyl and ad).heterocyclyl (wherein the point of attachment for the ad). heterocyclylat R₈ is a carbon ring atom; and, the ad). heterocyclyl contains asingle nitrogen ring atom); wherein the ab). cycloalkyl, ac).cycloalkenyl and ad). heterocyclyl substituents and the cycloalkylportion of the aa). substituent are optionally substituted with one totwo substituents independently selected from the group consisting ofba). C₁₋₄ alkyl, bc). carbonyl (substituted with a substituent selectedfrom the group consisting of C₁₋₄ alkyl, aryl, aryl(C₁₋₄)alkyl andaryl(C₂₋₄)alkenyl) and bd). aryl; wherein the bd). aryl substituent andthe aryl portions of the bc). substituent are optionally substitutedwith one to two substituents independently selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, di(C₁₋₄ alkyl)amino, halogen,hydroxy and (halo)₁₋₃(C₁₋₄)alkyl.

More preferably, R₈ is selected from the group consisting of aa).adamant-1-ylmethyl, ab). cyclopentyl, ab). cyclohexyl, ac).cyclohexenyl, ad). pyrrolidinyl and ad). piperidinyl (wherein the pointof attachment for pyrrolidinyl and piperidinyl at R₈ is a carbon ringatom); wherein ab). cyclohexyl, ac). cyclohexenyl, ad). pyrrolidinyl andad). piperidinyl are optionally substituted with one to two substituentsindependently selected from the group consisting of ba). C₁₋₄ alkyl,bc). carbonyl (substituted with a substituent selected from the groupconsisting of C₁₋₄ alkyl, aryl, aryl(C₁₋₄)alkyl and aryl(C₂₋₄)alkenyl)and bd). aryl; wherein the bd). aryl substituent and the aryl portionsof the bc). substituent are optionally substituted with one to twosubstituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ alkoxy, di(C₁₋₄ alkyl)amino, halogen, hydroxy and(halo)₁₋₃(C₁₋₄)alkyl.

Most preferably, R₈ is selected from the group consisting of aa).adamant-1-ylmethyl, ab). cyclopentyl, ab). cyclohexyl, ac).cyclohexenyl, ad). pyrrolidinyl and ad). piperidinyl (wherein the pointof attachment for pyrrolidinyl and piperidinyl at R₈ is a carbon ringatom); wherein ab). cyclohexyl, ac). cyclohexenyl, ad). pyrrolidinyl andad). piperidinyl are optionally substituted with one to two substituentsindependently selected from the group consisting of ba). methyl, ba).t-butyl, bc). methylcarbonyl, bc). i-propylcarbonyl, bc).phenylcarbonyl, bc). naphthalenylcarbonyl, bc). phenethylcarbonyl, bc).phenethenylcarbonyl and bd). phenyl; and, wherein the bd). phenylsubstituent and the phenyl and naphthalenyl portions of the bc).substituent are optionally substituted with one to two substituentsindependently selected from the group consisting of methyl, methoxy,N,N-dimethylamino, fluorine, bromine, hydroxy and trifluoromethyl.

Embodiments of the present invention include those compounds wherein R₂and R₃ are attached to the benzene ring (shown in Formula I) on adjacentcarbon atoms. Preferred embodiments of the present invention includethose compounds wherein R₂ and R₃ are independently selected from thegroup consisting of ca). hydrogen, cb). C₁₋₄ alkyl, cc). C₁₋₄ alkoxy,cd). C₂₋₄ alkenyl, ce). amino (substituted with two substituentsindependently selected from the group consisting of hydrogen and C₁₋₄alkyl), cf. halogen and cg). hydroxy; optionally R₂ and R₃ together format least one ring fused to the benzene ring; thereby providing amultiple ring system; wherein the multiple ring system is selected fromthe group consisting of naphthalene and anthracene; and, wherein themultiple ring system can optionally be substituted with one to foursubstituents independently selected from the group consisting of da).C₁₋₄ alkyl, db). C₁₋₄ alkoxy, dc). amino (substituted with twosubstituents independently selected from the group consisting ofhydrogen and C₁₋₄ alkyl), dd). halogen and de). hydroxy.

More preferably, R₂ and R₃ are attached to the benzene ring on adjacentcarbon atoms and independently selected from the group consisting ofca). hydrogen, cb). C₁₋₄ alkyl, cd). C₂₋₄ alkenyl, cf). halogen and cg).hydroxy; optionally, R₂ and R₃ together form at least one ring fused tothe benzene ring; thereby providing a multiple ring system; wherein themultiple ring system is naphthalene; and, wherein the multiple ringsystem can optionally be substituted with one to four substituentsindependently selected from the group consisting of da). C₁₋₄ alkyl,db). C₁₋₄ alkoxy, dc). amino (substituted with two substituentsindependently selected from the group consisting of hydrogen and C₁₋₄alkyl), dd). halogen and de). hydroxy.

Most preferably, the multiple ring system is a non-substitutednaphthalene.

Embodiments of the present invention include those compounds wherein R₄is selected from the group consisting of aryl and heteroaryl optionallysubstituted with one to two substituents independently selected from thegroup consisting of C₁₋₄ alkyl, amino (substituted with two substituentsindependently selected from the group consisting of hydrogen and C₁₋₄alkyl), cyano, halogen, hydroxy and (halo)₁₋₃(C₁₋₈)alkyl.

Preferably, R₄ is selected from the group consisting of aryl andheteroaryl (wherein heteroaryl is optionally substituted with one to twosubstituents independently selected from the group consisting of C₁₋₄alkyl, amino (substituted with two substituents independently selectedfrom the group consisting of hydrogen and C₁₋₄ alkyl), cyano, halogen,hydroxy and (halo)₁₋₃(C₁₋₈)alkyl).

More preferably, R₄ is selected from the group consisting of phenyl,naphthalenyl and benzothienyl (wherein benzothienyl is optionallysubstituted with one to two halogen substituents).

Most preferably, R₄ is selected from the group consisting of phenyl,naphthalenyl and benzothienyl (wherein benzothienyl is optionallysubstituted with a chloro substituent).

Embodiments of the present invention include those compounds wherein R₅is selected from the group consisting of hydrogen and C₁₋₄ alkyl(optionally substituted on a terminal carbon atom with a substituentselected from the group consisting of amino (substituted with twosubstituents independently selected from the group consisting ofhydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy).

Preferably, R₅ is selected from the group consisting of hydrogen andC₁₋₄ alkyl.

More preferably, R₅ is selected from the group consisting of hydrogenand methyl.

Most preferably, R₅ is hydrogen.

Preferred embodiments of the present invention include those compoundswherein R₆ is selected from the group consisting of C₁₋₄ alkyl,aryl(C₁₋₄)alkyl, C₁₋₄ alkoxy, aryl(C₁₋₄)alkoxy, C₂₋₄ alkenyl, C₂₋₄alkenyloxy, aryl(C₂₋₄)alkenyl, aryl(C₂₋₄)alkenyloxy, aryl, aryloxy andhydroxy.

More preferably, R₆ is selected from the group consisting of methyl,methoxy, phenyloxy and hydroxy.

Most preferably, R₆ is selected from the group consisting of methyl andhydroxy.

Preferred embodiments of the present invention include those compoundswherein Y is not present and X is one substituent attached by adouble-bond selected from the group consisting of O, S, imino,(C₁₋₄)alkylimino and hydroxyimino.

More preferably, Y is not present and X is one substituent attached by adouble-bond selected from the group consisting of O, imino andhydroxyimino.

Most preferably, Y is not present and X is O attached by a double-bond.

Preferred embodiments of the present invention include those compoundswherein Z is selected from the group consisting of hydrogen and C₁₋₄alkyl.

More preferably, Z is hydrogen.

Embodiments of the present invention include those compounds of Formula(Ia) shown in Table 1.

TABLE 1 Formula (Ia)

wherein R₅, R₇ and R₈ are dependently selected from the group consistingof: Cpd R₇ R₈  1 CH₃ 4-phenylcyclohexyl  2 CH₃1-(2-naphthalenylcarbonyl)-4-piperidinyl  3 CH₃1-[(6-methoxy-2-naphthalenyl)carbonyl]-3-pyrrolidinyl  4 CH₃1-[(6-bromo-2-naphthalenyl)carbonyl]-4-piperidinyl  5 CH₃1-[3-(4-fluorophenyl)-1-oxo-2-propenyl]-3-pyrrolidinyl  6 CH₃1-[1-oxo-3-phenyl-2-propenyl]-4-piperidinyl  9 CH₃1-[3-(4-methylphenyl)-1-oxo-2-propenyl]-4-piperidinyl 10 CH₃1-[1-oxo-3-[4-(trifluoromethyl)phenyl]-2-propenyl]-4- piperidinyl 13 CH₃1-[3-[4-(dimethylamino)phenyl]-1-oxo-2-propenyl]-4- piperidinyl 15 CH₃1-benzoyl-4-piperidinyl 17 CH₃ Cyclohexyl 18 CH₃1-[1-oxo-3-[4-(trifluoromethyl)phenyl]propyl]-4-piperidinyl 20 CH₃1-(2-methyl-1-oxopropyl)-4-piperidinyl 21 CH₃ Cyclopentyl 22 CH₃4-(1,1-dimethylethyl)cyclohexyl 24 CH₃1-[(6-hydroxy-2-naphthalenyl)carbonyl]-4-piperidinyl 26 CH₃1-acetyl-4-piperidinyl 27 CH₃ 4-methylcyclohexyl 28 CH₃adamant-1-ylmethyl 29 CH₃ 4-phenyl-3-cyclohexen-1-yl And, 30 H1-(2-naphthalenylcarbonyl)-4-piperidinyl and racemates, enantiomers,diastereomers and salts thereof.

Embodiments of the present invention include those compounds of Formula(Ib) shown in Table 2.

TABLE 2 Formula (Ib)

wherein R₁ is selected from the group consisting of: Cpd R₁  74-phenyl-1-piperidinyl  8 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl12 4-(4-methoxyphenyl)-1-piperidinyl 144-(3-methoxyphenyl)-1-piperidinyl 16 4-(2-benzothiazolyl)-1-piperidinyl19 3-phenyl-1-pyrrolidinyl and, 25 3-(2-phenylethyl)-1-pyrrolidinyl andracemates, enantiomers, diastereomers and salts thereof.

Embodiments of the present invention include those compounds of Formula(Ic) shown in Table 3.

TABLE 3 Formula (Ic)

wherein R₂, R₃, R₄, R₅ and R₆ are dependently selected from the groupconsisting of: Cpd R₂ R₃ R₄ R₅ R₆ 11 taken together to form phenyl H OHphenyl 23 taken together to form 1-naphthalenyl CH₃ OH phenyl 31 H H1-naphthalenyl H OH 32 taken together to form 1-naphthalenyl H CH₃phenyl And, 33 taken together to form 5-chloro-benzo[b]thien-3-yl H OHphenyl and racemates, enantiomers, diastereomers and salts thereof.

In embodiments for Formula (II) the preferred embodiments of R₂, R₃, R₄,R₅ and R₆ are as previously described.

Preferably, R₁₀ is selected from the group consisting of

-   a). sulfonyl substituted with a substituent selected from the group    consisting of C₁₋₈ alkyl, aryl, aryl(C₁₋₈)alkyl, aryl(C₂₋₈)alkenyl,    cycloalkyl, cycloalkenyl, heterocycl, heteroaryl,    heteroaryl(C₁₋₈)alkyl and heteroaryl(C₂₋₈)alkenyl;-   b). carbonyl substituted with a substituent selected from the group    consisting of C₁₋₈ alkyl, aryl, aryl(C₁₋₈)alkyl, aryl(C₂₋₈)alkenyl,    cycloalkyl, cycloalkenyl, heterocycl heteroaryl,    heteroaryl(C₁₋₈)alkyl, heteroaryl(C₂₋₈)alkenyl, —OR₁₁ and amino    (with two substituents independently selected from the group    consisting of hydrogen, C₁₋₈ alkyl, aryl, arylC₁₋₈ alkyl,    arylcarbonyl, arylC₁₋₈ alkyl carbonyl and heteroaryl C₁₋₈ alkyl);-   c). C₁₋₈ alkyl optionally substituted on a terminal carbon atom with    a substituent selected from the group consisting of aryl,    cycloalkyl, cycloalkenyl, heterocycl, heteroaryl, (halo)₁₋₃,    hydroxy, —C(O)R₁₂ and amino (with two substituents independently    selected from the group consisting of hydrogen, C₁₋₈ alkyl, arylC₁₋₈    alkyl, arylcarbonyl, arylC₁₋₈ alkyl carbonyl and heteroaryl C₁₋₈    alkyl);-   d). aryl; and-   e). heteroaryl;-   wherein the heterocycl, cycloalkyl, cycloalkenyl portion of a).,    b)., and c). are optionally substituted with one to two substituents    independently selected from the group consisting of:    -   ea). oxo    -   eb). carbonyl substituted with a substituent selected from the        group consisting of C₁₋₈ alkyl, aryl, aryl(C₁₋₈)alkyl,        aryl(C₂₋₈)alkenyl, cycloalkyl, cycloalkenyl, heterocycl        heteroaryl, heteroaryl(C₁₋₈)alkyl, heteroaryl(C₂₋₈)alkenyl and        amino (with two substituents independently selected from the        group consisting of hydrogen, C₁₋₈ alkyl, arylC₁₋₈ alkyl,        arylcarbonyl, arylC₁₋₈ alkyl carbonyl and heteroaryl C₁₋₈        alkyl);    -   ec). C₁₋₈ alkyl optionally substituted with a substituent        selected from the group consisting of amino (with two        substituents independently selected from the group consisting of        hydrogen, C₁₋₈ alkyl, arylC₁₋₈ alkyl, arylcarbonyl, arylC₁₋₁₈        alkyl carbonyl and heteroaryl C₁₋₈ alkyl), aryl, cycloalkyl,        cycloalkenyl, heterocycl, heteroaryl, (halo)₁₋₃, and hydroxy;    -   ed). aryl; and    -   ef). (halo)₁₋₃-   wherein the aryl portion of the a)., b)., c)., ec). and ed).    substituents, the heteroaryl portion of the a)., b)., c). and ec).    substituents and the d). aryl and e). heteroaryl substituents are    optionally substituted with one to four substituents independently    selected from the group consisting of-   fa). C₁₋₄ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of aryl,    cycloalkyl, cycloalkenyl, heterocycl, heteroaryl, (halo)₁₋₃,    hydroxy, —C(O)R₁₂ and amino (with two substituents independently    selected from the group consisting of hydrogen, C₁₋₈ alkyl, arylC₁₋₈    alkyl, arylcarbonyl, arylC₁₋₈ alkyl carbonyl and heteroaryl C₁₋₈    alkyl);-   fb). C₂₋₄ alkenyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of amino (with    two substituents independently selected from the group consisting of    hydrogen and C₁₋₈ alkyl), (halo)₁₋₃ and hydroxy;-   fc). C₁₋₄ alkoxy optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of (halo)₁₋₃    and hydroxy;-   fd). cycloalkyl,-   fe). heterocyclyl,-   ff). aryl optionally substituted with one to four substituents    independently selected from the group consisting of C₁₋₈ alkyl and    halogen;-   fg). heteroaryl,-   fh). hydroxy;-   fi). hydroxy;-   fj). nitro; and-   fk). (halo)₁₋₃;-   wherein the aryl portion of the arylC₁₋₈ alkyl, arylcarbonyl,    arylC₁₋₈ alkyl carbonyl of fa). are optionally substituted with one    to four substituents independently selected from the group    consisting of C₁₋₄ alkyl (optionally substituted on a terminal    carbon atom with a substituent selected from the group consisting of    amino (substituted with two substituents independently selected from    the group consisting of hydrogen and C₁₋₈ alkyl), (halo)₁₋₃ and    hydroxy), C₁₋₄ alkoxy (optionally substituted on a terminal carbon    atom with a substituent selected from the group consisting of    (halo)₁₋₃), amino (substituted with two substituents independently    selected from the group consisting of hydrogen and C₁₋₄ alkyl),    halogen, hydroxy and nitro.

Preferably, R₁₁ is selected from the group consisting of:

-   aa). C₁₋₄ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of cycloalkyl,    heterocyclyl, aryl, heteroaryl, amino (with two substituents    independently selected from the group consisting of hydrogen and    C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy;-   wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl portions    of the aa). substituent are optionally substituted with one to four    substituents independently selected from the group consisting of:-   ba). C₁₋₄ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of amino (with    two substituents independently selected from the group consisting of    hydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy;-   bb). C₁₋₄ alkoxy optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of carboxyl,    (halo)₁₋₃ and hydroxy;-   bc). carbonyl substituted with a substituent selected from the group    consisting of C₁₋₄ alkyl, aryl, aryl(C₁₋₄)alkyl, aryl(C₂₋₄)alkenyl,    heteroaryl, heteroaryl(C₁₋₄)alkyl and heteroaryl(C₂₋₄)alkenyl;-   bd). aryl;-   be). heteroaryl;-   bf). amino substituted with two substituents independently selected    from the group consisting of hydrogen and C₁₋₄ alkyl;-   bh). (halo)₁₋₃;-   bi). hydroxy; and-   bk). heterocyclyl optionally substituted with one to two oxo    substituents; and,-   wherein the bd). aryl, be). heteroaryl and bk). heterocyclyl    substituents and the aryl and heteroaryl portions of the bc).    substituent are optionally substituted with one to four substituents    independently selected from the group consisting of C₁₋₄ alkyl    (optionally substituted on a terminal carbon atom with a substituent    selected from the group consisting of amino (substituted with two    substituents independently selected from the group consisting of    hydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy), C₁₋₄ alkoxy    (optionally substituted on a terminal carbon atom with a substituent    selected from the group consisting of (halo)₁₋₃), amino (substituted    with two substituents independently selected from the group    consisting of hydrogen and C₁₋₄ alkyl), halogen, hydroxy and nitro;    Preferably, R₁₂ is selected from the group consisting of C₁₋₄ alkyl,    aryl, aryl(C₁₋₄)alkyl, aryl(C₂₋₄)alkenyl, cycloalkyl, cycloalkenyl,    heterocycl heteroaryl, heteroaryl(C₁₋₄)alkyl,    heteroaryl(C₂₋₄)alkenyl, —OR₁₁ and amino (with two substituents    independently selected from the group consisting of hydrogen, C₁₋₄    alkyl, arylC₁₋₄ alkyl, arylcarbonyl, arylC₁₋₄ alkyl carbonyl and    heteroaryl C₁₋₄ alkyl); wherein the aryl, the heteroaryl portion of    R₁₂ are optionally substituted with one to four substituents    independently selected from the group consisting of:-   fa). C₁₋₄ alkyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of aryl,    cycloalkyl, cycloalkenyl, heterocycl, heteroaryl, (halo)₁₋₃,    hydroxy, —C(O)R₁₁ and amino (with two substituents independently    selected from the group consisting of hydrogen, C₁₋₈ alkyl, arylC₁₋₄    alkyl, arylcarbonyl, arylC₁₋₄ alkyl carbonyl and heteroaryl C₁₋₄    alkyl);-   fb). C₂₋₄ alkenyl optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of amino (with    two substituents independently selected from the group consisting of    hydrogen and C₁₋₄ alkyl), (halo)₁₋₃ and hydroxy;-   fc). C₁₋₄ alkoxy optionally substituted on a terminal carbon atom    with a substituent selected from the group consisting of (halo)₁₋₃    and hydroxy;-   fd). cycloalkyl,-   fe). heterocyclyl,-   ff). aryl optionally substituted with one to four substituents    independently selected from the group consisting of C₁₋₄ alkyl and    halogen;-   fg). heteroaryl,-   fh). (halo)₁₋₃;-   fi). hydroxy; and-   fj). nitro;-   wherein the aryl portion of the arylC₁₋₈ alkyl, arylcarbonyl,    arylC₁₋₈ alkyl carbonyl of fa). are optionally substituted with one    to four substituents independently selected from the group    consisting of C₁₋₄ alkyl (optionally substituted on a terminal    carbon atom with a substituent selected from the group consisting of    amino (substituted with two substituents independently selected from    the group consisting of hydrogen and C₁₋₈ alkyl), (halo)₁₋₃ and    hydroxy), C₁₋₄ alkoxy (optionally substituted on a terminal carbon    atom with a substituent selected from the group consisting of    (halo)₁₋₃), amino (substituted with two substituents independently    selected from the group consisting of hydrogen and C₁₋₄ alkyl),    halogen, hydroxy and nitro;

Embodiments of the present invention include those compounds of Formula(IIa) shown in Table 4.

TABLE 24

Cpd R₁₀ 37 naphthalene-2-yl-acetyl 38 2-naphthoyl 39 1-(4-hydroxyphenyl)40 1-(4-methoxyphenyl) 41N-[5-(sulfonyl)-thiophene-2-ylmethyl]-benzamide 426-chloro-5-sulfonyl-imidazo[2,1-b]thiazole 43 Naphthyl-2-aminocarbonyl44 1-(4-fluorophenyl) and racemates, enantiomers, diastereomers andsalts thereof.

The compounds of the present invention may also be present in the formof pharmaceutically acceptable salts. For use in medicine, the salts ofthe compounds of this invention refer to non-toxic “pharmaceuticallyacceptable salts.” FDA approved pharmaceutically acceptable salt forms(Ref. International J. Pharm. 1986, 33, 201-217; J. Pharm. Sci., 1977,January, 66(1), p 1) include pharmaceutically acceptable acidic/anionicor basic/cationic salts.

Pharmaceutically acceptable acidic/anionic salts include, and are notlimited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate,bromide, calcium edetate, camsylate, carbonate, chloride, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isethionate, lactate, lactobionate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate,tannate, tartrate, teoclate, tosylate and triethiodide. Organic orinorganic acids also include, and are not limited to, hydriodic,perchloric, sulfuric, phosphoric, propionic, glycolic, methanesulfonic,hydroxyethanesulfonic, oxalic, 2-naphthalenesulfonic, p-toluenesulfonic,cyclohexanesulfamic, saccharinic or trifluoroacetic acid.

Pharmaceutically acceptable basic/cationic salts include, and are notlimited to aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (alsoknown as tris(hydroxymethyl)aminomethane, tromethane or “TRIS”),ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calciumhydroxide, chloroprocaine, choline, choline bicarbonate, cholinechloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium,LiOMe, L-lysine, magnesium, meglumine, NH₃, NH₄OH, N-methyl-D-glucamine,piperidine, potassium, potassium-t-butoxide, potassium hydroxide(aqueous), procaine, quinine, SEH, sodium, sodium carbonate,sodium-2-ethylhexanoate, sodium hydroxide, triethanolamine (TEA) orzinc.

Compounds of the present invention may be contacted with apharmaceutically acceptable cation selected from the group consisting ofaluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known astris(hydroxymethyl)aminomethane, tromethane or “TRIS”), ammonia,benzathine, t-butylamine, calcium, calcium gluconate, calcium hydroxide,chloroprocaine, choline, choline bicarbonate, choline chloride,cyclohexylamine, diethanolamine, ethylenediamine, lithium, LiOMe,L-lysine, magnesium, meglumine, NH₃, NH₄OH, N-methyl-D-glucamine,piperidine, potassium, potassium-t-butoxide, potassium hydroxide(aqueous), procaine, quinine, SEH, sodium, sodium carbonate,sodium-2-ethylhexanoate, sodium hydroxide, triethanolamine (TEA) andzinc to form a salt.

Preferred cations for use with the instant compounds are selected fromthe group consisting of benzathine, t-butylamine, calcium gluconate,calcium hydroxide, choline bicarbonate, choline chloride,cyclohexylamine, diethanolamine, ethylenediamine, LiOMe, L-lysine, NH₃,NH₄OH, N-methyl-D-glucamine, piperidine, potassium-t-butoxide, potassiumhydroxide (aqueous), procaine, quinine, sodium carbonate,sodium-2-ethylhexanoate, sodium hydroxide, triethanolamine andtromethane.

More preferably, cations for use with the instant compounds are selectedfrom the group consisting of t-butylamine, NH₄OH and tromethane.

Most preferably, the cation for use with the instant compounds istromethane.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds, which are readily convertiblein vivo into an active compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or a prodrug compound which would be obviouslyincluded within the scope of the invention although not specificallydisclosed including, but not limited to diphenylphosphonate ordiphenylphosphinate esters of certain of the instant compounds.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985. Phosphonic acid prodrugs (as describedin De Lombaert S., et al, Non-Peptidic Inhibitors of NeutralEndopeptidase 24.11; Design and Pharmacology of Orally ActivePhosphonate Prodrugs, Bioorganic and Medicinal Chemistry Letters, 1995,5(2), 151-154; and, De Lombaert S., et al, N-Phosphonomethyl Dipeptidesand Their Phosphonate Prodrugs, a New Generation Neutral Endopeptidase(NEP, EC 3.424.11) Inhibitors, J. Med. Chem., 1994, 37, 498-511) andphosphinic acid prodrugs are intended to be included within the scope ofthe present invention.

The compounds according to this invention may have at least one chiralcenter and thus may exist as enantiomers. In addition, the compounds ofthe present invention may also possess two or more chiral centers andthus may also exist as diastereomers. Where the processes for thepreparation of the present compounds give rise to a mixture ofstereoisomers, these isomers may be separated by conventional techniquessuch as preparative chromatography. Accordingly, the compounds may beprepared as a racemic mixture or, by either enantiospecific synthesis orresolution, as individual enantiomers. The compounds may, for example,be resolved from a racemic mixture into their component racemates bystandard techniques, such as the formation of diastereomeric pairs bysalt formation with an optically active base, followed by fractionalcrystallization and regeneration of the compounds of this invention. Theracemic mixture may also be resolved by formation of diastereomericesters or amides, followed by chromatographic separation and removal ofthe chiral auxiliary. Alternatively, the compounds may be resolved usinga chiral HPLC column. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The compounds according to this invention wherein Z forms a double bondwith the carbon of attachment for X, Y is not present and X is hydroxymay have at least one keto-enol tautomeric form and thus may exist inequilibrium as geometric isomers. It is to be understood that all suchisomers and mixtures thereof are encompassed within the scope of thepresent invention.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown in the art.

Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

As used herein, unless otherwise noted, “alkyl” whether used alone or aspart of a substituent group refers to straight and branched carbonchains having 1 to 8 carbon atoms or any number within this range. Theterm “alkoxy” refers to an —O-alkyl substituent group, wherein alkyl isas defined supra. Similarly, the terms “alkenyl” and “alkynyl” refer tostraight and branched carbon chains having 2 to 8 carbon atoms or anynumber within this range, wherein an alkenyl chain has at least onedouble bond in the chain and an alkynyl chain has at least one triplebond in the chain. An alkyl and alkoxy chain may be substituted on aterminal carbon atom or, when acting as a linking group, within thecarbon chain.

The term “cycloalkyl” refers to saturated, monocyclic or polycyclichydrocarbon rings of from 3 to 20 carbon atom members (preferably from 3to 12 carbon atom members). Further, a cycloalkyl ring may optionally befused to one or more cycloalkyl rings. Examples of such rings include,and are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or adamantyl.

The term “cycloalkenyl” refers to partially unsaturated, nonaromaticmonocyclic or polycyclic hydrocarbon rings of 3 to 20 carbon atommembers (preferably from 3 to 12 carbon atom members). Typically, a 3 to5 member ring contains one double bond and a 6 to 9 member ring containsmultiple double bonds. Further, a cycloalkenyl ring may optionally befused to one or more cycloalkyl rings or cycloalkenyl rings. Examples ofsuch rings include, and are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, or cycloheptenyl.

The term “heterocyclyl” refers to a nonaromatic cyclic ring of 5 to 8members in which 1 to 4 members are nitrogen or a nonaromatic cyclicring of 5 to 8 members in which zero, one or two members are nitrogenand one member is oxygen or sulfur; wherein, optionally, the ringcontains zero, one or two unsaturated bonds. Alternatively, theheterocyclyl ring may be fused to a benzene ring (benzo fusedheterocyclyl), a 5 or 6 membered heteroaryl ring (containing one of O, Sor N and, optionally, one additional nitrogen), a 5 to 7 memberedcycloalkyl or cycloalkenyl ring, a 5 to 7 membered heterocyclyl ring (ofthe same definition as above but absent the option of a further fusedring) or fused with the carbon of attachment of a cycloalkyl,cycloalkenyl or heterocyclyl ring to form a spiro moiety. For instantcompounds of the invention, the carbon atom ring members that form theheterocyclyl ring are fully saturated. Other compounds of the inventionmay have a partially saturated heterocyclyl ring. Additionally, theheterocyclyl can be bridged to form bicyclic rings. Preferred partiallysaturated heterocyclyl rings may have from one to two double bonds. Suchcompounds are not considered to be fully aromatic and are not referredto as heteroaryl compounds. Examples of heterocyclyl groups include, andare not limited to, pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or3-pyrrolinyl), pyrrolidinyl, 2-imidazolinyl, imidazolidinyl,2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyland piperazinyl. In the present invention, when R₁ is selected fromheterocyclyl, the term “heterocyclyl” refers to a nonaromatic cyclicring of 5 to 8 members in which 1 to 4 members are nitrogen; wherein,the point of attachment for the heterocyclyl ring at R₁ is a nitrogenring member; and, wherein optionally the ring contains zero, one (for 5and 6 member rings) or two (for 6, 7 and 8 member rings) unsaturatedbonds.

The term “aryl” refers to an unsaturated, aromatic monocyclic ring of 6carbon members or to an unsaturated, aromatic polycyclic ring of from 10to 20 carbon members. Further, an aryl ring may optionally be fused toone or more benzene rings (benzo fused aryl), cycloalkyl rings (e.g.benzo fused cycloalkyl) or cycloalkenyl rings (e.g. benzo fusedcycloalkenyl) wherein, for the purpose of these definitions, thecycloalkyl rings and cycloalkenyl rings may be fused to an additionalbenzene ring (to provide fused multiple ring systems such as fluorene).Examples of such aryl rings include, and are not limited to, phenyl,naphthalenyl, fluorenyl, indenyl or anthracenyl.

The term “heteroaryl” refers to an aromatic ring of 5 or 6 memberswherein the ring consists of carbon atoms and has at least oneheteroatom member. Suitable heteroatoms include nitrogen, oxygen orsulfur. In the case of 5 membered rings, the heteroaryl ring containsone member of nitrogen, oxygen or sulfur and, in addition, may containup to two additional nitrogens. In the case of 6 membered rings, theheteroaryl ring may contain from one to three nitrogen atoms. For thecase wherein the 6 member ring has three nitrogens, at most two nitrogenatoms are adjacent. Optionally, the heteroaryl ring is fused to abenzene ring (benzo fused heteroaryl), a 5 or 6 membered heteroaryl ring(containing one of O, S or N and, optionally, one additional nitrogen),a 5 to 7 membered alicyclic ring or a 5 to 7 membered heterocyclo ring(as defined supra but absent the option of a further fused ring).Examples of heteroaryl groups include, and are not limited to, furyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; fused heteroarylgroups include indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl,indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl,benzothiadiazolyl, benzotriazolyl, quinolizinyl, quinolinyl,isoquinolinyl or quinazolinyl.

The term “arylalkyl” means an alkyl group substituted with an aryl group(e.g., benzyl, phenethyl). Similarly, the term “arylalkoxy” indicates analkoxy group substituted with an aryl group (e.g., benzyloxy).

As used herein, the term “carboxyl” refers to the linking group —C(O)O—or (when used accordingly) to the substituent —COOH; the term “imino”refers to the substituent HN═.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g., arylalkyl, alkylamino) it shallbe interpreted as including those limitations given above for “alkyl”and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆) shall referindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger substituent in which alkyl appears as itsprefix root. However, for clarity in the terms “C₉-C₁₄ benzo fusedcycloalkyl”, “C₉-C₁₄ benzo fused cycloalkenyl”, “C₉-C₁₄ benzo fusedaryl”; C₉-C₁₄ refers to the number of carbon atoms both in the benzene.ring (6) and the number of atoms in the ring fused to the benzene ring,but does not include carbon atoms that may be pendent from thesemultiple ring systems. The amount of substituents attached to a moiety“optionally substituted with one to five substituents” is limited tothat amount of open valences on the moiety available for substitution.

In general, under standard nomenclature rules used throughout thisdisclosure, the terminal portion of the designated side chain isdescribed first followed by the adjacent functionality toward the pointof attachment. Thus, for example, a “phenylC₁-C₆ alkylamidoC₁-C₆alkyl”substituent refers to a group of the formula:

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

Illustrative of the invention is a composition comprising apharmaceutically acceptable carrier and any of the compounds describedabove. Also illustrative of the invention is a composition made bymixing any of the compounds described above and a pharmaceuticallyacceptable carrier. A further illustration of the invention is a processfor making a composition comprising mixing any of the compoundsdescribed above and a pharmaceutically acceptable carrier. The presentinvention also provides compositions comprising one or more compounds ofthis invention in association with a pharmaceutically acceptablecarrier.

The compounds of the present invention are useful serine proteaseinhibitors (in particular, inhibitors of cathepsin G and chymase) usefulfor treating inflammatory and serine protease mediated disorders. Someof these disorders include, inflammatory and serine protease mediateddisorders include, and are not limited to, pulmonary inflammatoryconditions, chronic obstructive pulmonary diseases, asthma, pulmonaryemphysema, bronchitis, psoriasis, allergic rhinitis, viral rhinitis,ischemia, arthritis, glomerulonephritis, postoperative adhesionformation and reperfusion injury. These compounds would be useful intreating disease states caused by angiotensin II including but notlimited to hypertension, hypercardia myocardial infarction,arteriosclerosis, diabetic and non-diabetic retinopathy, vascularrestenosis and the like. Additionally, these compounds can be used forimmune modulation. The utility of the compounds to treat inflammatoryand serine protease mediated disorders can be determined according tothe procedures described herein.

An embodiment of the invention is a method for treating inflammatory andserine protease mediated disorders in a subject in need thereof whichcomprises administering to the subject a therapeutically effectiveamount of any of the compounds or compositions described above. Alsoincluded in the invention is the use of a compound of Formula (I) forthe preparation of a medicament for treating an inflammatory or serineprotease mediated disorder in a subject in need thereof. The term“treating” as used herein refers to a method for improving, halting,retarding or palliating an inflammatory or serine protease mediateddisorder in the subject in need thereof. All such methods of treatmentare intended to be within the scope of the present invention.

In accordance with the methods of the present invention, the individualcomponents of the compositions described herein can also be administeredseparately at different times during the course of therapy orconcurrently in divided or single combination forms. The instantinvention is therefore to be understood as embracing all such regimes ofsimultaneous or alternating treatment and the term “administering” is tobe interpreted accordingly.

The term “subject” as used herein, refers to an animal (preferably, amammal; most preferably, a human) who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or human,that is being sought by a researcher, veterinarian, medical doctor, orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

To prepare the compositions of this invention, one or more compounds ofFormula (I) or salt thereof as the active ingredient, is intimatelyadmixed with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques, which carrier may take a widevariety of forms depending of the form of preparation desired foradministration (e.g. oral or parenteral). Suitable pharmaceuticallyacceptable carriers are well known in the art. Descriptions of some ofthese pharmaceutically acceptable carriers may be found in The Handbookof Pharmaceutical Excipients, published by the American PharmaceuticalAssociation and the Pharmaceutical Society of Great Britain.

Methods of formulating compositions have been described in numerouspublications such as Pharmaceutical Dosage Forms: Tablets, SecondEdition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al;Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, editedby Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems,Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

In preparing a composition of the present invention in liquid dosageform for oral, topical, inhalation/insufflation and parenteraladministration, any of the usual pharmaceutical media or excipients maybe employed. Thus, for liquid dosage forms, such as suspensions (i.e.colloids, emulsions and dispersions) and solutions, suitable carriersand additives include but are not limited to pharmaceutically acceptablewetting agents, dispersants, flocculation agents, thickeners, pH controlagents (i.e. buffers), osmotic agents, coloring agents, flavors,fragrances, preservatives (i.e. to control microbial growth, etc.) and aliquid vehicle may be employed. Not all of the components listed abovewill be required for each liquid dosage form.

In solid oral preparations such as, for example, powders, granules,capsules, caplets, gelcaps, pills and tablets (each including immediaterelease, timed release and sustained release formulations), suitablecarriers and additives include but are not limited to diluents,granulating agents, lubricants, binders, glidants, disintegrating agentsand the like. Because of their ease of administration, tablets andcapsules represent the most advantageous oral dosage unit form, in whichcase solid pharmaceutical carriers are obviously employed. If desired,tablets may be sugar coated, gelatin coated, film coated or entericcoated by standard techniques.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, lozenges, sterileparenteral solutions or suspensions, metered aerosol or liquid sprays,drops, ampoules, autoinjector devices or suppositories foradministration by oral, intranasal, sublingual, intraocular,transdermal, parenteral, rectal, vaginal, inhalation or insufflationmeans. Alternatively, the composition may be presented in a formsuitable for once-weekly or once-monthly administration; for example, aninsoluble salt of the active compound, such as the decanoate salt, maybe adapted to provide a depot preparation for intramuscular injection.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltabletting ingredients such as diluents, binders, adhesives,disintegrants, lubricants, antiadherents and glidants. Suitable diluentsinclude, but are not limited to, starch (i.e. corn, wheat, or potatostarch, which may be hydrolized), lactose (granulated, spray dried oranhydrous), sucrose, sucrose-based diluents (confectioner's sugar;sucrose plus about 7 to 10 weight percent invert sugar; sucrose plusabout 3 weight percent modified dextrins; sucrose plus invert sugar,about 4 weight percent invert sugar, about 0.1 to 0.2 weight percentcornstarch and magnesium stearate), dextrose, inositol, mannitol,sorbitol, microcrystalline cellulose (i.e. AVICEL™ microcrystallinecellulose available from FMC Corp.), dicalcium phosphate, calciumsulfate dihydrate, calcium lactate trihydrate and the like. Suitablebinders and adhesives include, but are not limited to accacia gum, guargum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics(i.e. methylcellulose, sodium carboxymethylcellulose, ethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like),water soluble or dispersible binders (i.e. alginic acid and saltsthereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e.TYLOSE™ available from Hoechst Celanese], polyethylene glycol,polysaccharide acids, bentonites, polyvinylpyrrolidone,polymethacrylates and pregelatinized starch) and the like. Suitabledisintegrants include, but are not limited to, starches (corn, potato,etc.), sodium starch glycolates, pregelatinized starches, clays(magnesium aluminum silicate), celluloses (such as crosslinked sodiumcarboxymethylcellulose and microcrystalline cellulose), alginates,pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar,locust bean, karaya, pectin, and tragacanth gum), cross-linkedpolyvinylpyrrolidone and the like. Suitable lubricants and antiadherentsinclude, but are not limited to, stearates (magnesium, calcium andsodium), stearic acid, talc waxes, stearowet, boric acid, sodiumchloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate,sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium laurylsulfate and the like. Suitable glidants include, but are not limited to,talc, cornstarch, silica (i.e. CAB-O-SIL™ silica available from Cabot,SYLOID™ silica available from W. R. Grace/Davison, and AEROSIL™ silicaavailable from Degussa) and the like. Sweeteners and flavorants may beadded to chewable solid dosage forms to improve the palatability of theoral dosage form. Additionally, colorants and coatings may be added orapplied to the solid dosage form for ease of identification of the drugor for aesthetic purposes. These carriers are formulated with thepharmaceutical active to provide an accurate, appropriate dose of thepharmaceutical active with a therapeutic release profile.

Generally these carriers are mixed with the pharmaceutical active toform a solid preformulation composition containing a homogeneous mixtureof the pharmaceutical active of the present invention, or apharmaceutically acceptable salt thereof. Generally the preformulationwill be formed by one of three common methods: (a) wet granulation, (b)dry granulation and (c) dry blending. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from about 0.01 mg to about 500 mg of theactive ingredient of the present invention. The tablets or pillscontaining the novel compositions may also be formulated in multilayertablets or pills to provide a sustained or provide dual-releaseproducts. For example, a dual release tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer, which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric materials such as shellac, cellulose acetate, celluloseacetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetatesuccinate, methacrylate and ethylacrylate copolymers and the like.Sustained release tablets may also be made by film coating or wetgranulation using slightly soluble or insoluble substances in solution(which for a wet granulation acts as the binding agents) or low meltingsolids a molten form (which in a wet granulation may incorporate theactive ingredient). These materials include natural and syntheticpolymers waxes, hydrogenated oils, fatty acids and alcohols (i.e.beeswax, carnauba wax, cetyl alcohol, cetylstearyl alcohol, and thelike), esters of fatty acids metallic soaps, and other acceptablematerials that can be used to granulate, coat, entrap or otherwise limitthe solubility of an active ingredient to achieve a prolonged orsustained release product.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, but are not limited to aqueous solutions, suitably flavoredsyrups, aqueous or oil suspensions, and flavored emulsions with edibleoils such as cottonseed oil, sesame oil, coconut oil or peanut oil, aswell as elixirs and similar pharmaceutical vehicles. Suitable suspendingagents for aqueous suspensions, include synthetic and natural gums suchas, acacia, agar, alginate (i.e. propylene alginate, sodium alginate andthe like), guar, karaya, locust bean, pectin, tragacanth, and xanthangum, cellulosics such as sodium carboxymethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl celluloseand hydroxypropyl methylcellulose, and combinations thereof, syntheticpolymers such as polyvinyl pyrrolidone, carbomer (i.e.carboxypolymethylene), and polyethylene glycol; clays such as bentonite,hectorite, attapulgite or sepiolite; and other pharmaceuticallyacceptable suspending agents such as lecithin, gelatin or the like.Suitable surfactants include but are not limited to sodium docusate,sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polyoxamer 188, polyoxamer 235 and combinations thereof. Suitabledeflocculating or dispersing agent include pharmaceutical gradelecithins. Suitable flocculating agent include but are not limited tosimple neutral electrolytes (i.e. sodium chloride, potassium, chloride,and the like), highly charged insoluble polymers and polyelectrolytespecies, water soluble divalent or trivalent ions (i.e. calcium salts,alums or sulfates, citrates and phosphates (which can be used jointly informulations as pH buffers and flocculating agents). Suitablepreservatives include but are not limited to parabens (i.e. methyl,ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, quaternaryammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate,phenylethanol and the like. There are many liquid vehicles that may beused in liquid pharmaceutical dosage forms, however, the liquid vehiclethat is used in a particular dosage form must be compatible with thesuspending agent(s). For example, nonpolar liquid vehicles such as fattyesters and oils liquid vehicles are best used with suspending agentssuch as low HLB (Hydrophile-Lipophile Balance) surfactants,stearalkonium hectorite, water insoluble resins, water insoluble filmforming polymers and the like. Conversely, polar liquids such as water,alcohols, polyols and glycols are best used with suspending agents suchas higher HLB surfactants, clays silicates, gums, water solublecellulosics, water soluble polymers and the like. For parenteraladministration, sterile suspensions and solutions are desired. Liquidforms useful for parenteral administration include sterile solutions,emulsions and suspensions. Isotonic preparations which generally containsuitable preservatives are employed when intravenous administration isdesired.

Furthermore, compounds of the present invention can be administered inan intranasal dosage form via topical use of suitable intranasalvehicles or via transdermal skin patches, the composition of which arewell known to those of ordinary skill in that art. To be administered inthe form of a transdermal delivery system, the administration of atherapeutic dose will, of course, be continuous rather than intermittentthroughout the dosage regimen.

Compounds of the present invention can also be administered in a formsuitable for intranasal or inhalation therapy. For such therapy,compounds of the present invention are conveniently delivered in theform of a solution or suspension from a pump spray container that issqueezed or pumped or as an aerosol spray from a pressurized containeror a nebulizer (such as, a metered dose inhaler, a dry powder inhaler orother conventional or non-conventional modes or devices for inhalationdelivery) using a suitable propellant (such as, dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas). In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.The pressurized container or nebulizer may contain a solution orsuspension of the active compound. Capsules and cartridges (such as,those made from gelatin) for use in an inhaler or insufflator may beformulated containing a powder mix of a compound of the invention and asuitable powder base such as lactose or starch.

Compounds of the present invention can also be administered in the formof liposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, multilamellar vesicles and the like. Liposomes canbe formed from a variety of phospholipids, such as cholesterol,stearylamine, phosphatidylcholines and the like.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include, but are not limited to polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol,polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example, tohomopolymers and copolymers (which means polymers containing two or morechemically distinguishable repeating units) of lactide (which includeslactic acid d-, l- and meso lactide), glycolide (including glycolicacid), ε-caprolactone, p-dioxanone (1,4-dioxan-2-one), trimethylenecarbonate (1,3-dioxan-2-one), alkyl derivatives of trimethylenecarbonate, δ-valerolactone, β-butyrolactone, γ-butyrolactone,ε-decalactone, hydroxybutyrate, hydroxyvalerate, 1,4-dioxepan-2-one(including its dimer 1,5,8,12-tetraoxacyclotetradecane-7,14-dione),1,5-dioxepan-2-one, 6,6-dimethyl-1,4-dioxan-2-one, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels and blends thereof.

The therapeutically effective amount of a compound or compositionthereof may be from about 0.001 mg/Kg/dose to about 300 mg/Kg/dose.Preferably, the therapeutically effective amount may be from about 0.001mg/Kg/dose to about 100 mg/Kg/dose. More preferably, the therapeuticallyeffective amount may be from about 0.001 mg/Kg/dose to about 50mg/Kg/dose. Most preferably, the therapeutically effective amount may befrom about 0.001 mg/Kg/dose to about 30 mg/Kg/dose. Therefore, thetherapeutically effective amount of the active ingredient contained perdosage unit (e.g., tablet, capsule, powder, injection, suppository,teaspoonful and the like) as described herein will be in the range offrom about 1 mg/day to about 21,000 mg/day for a subject, for example,having an average weight of 70 Kg. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 and 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the subject to be treated.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, and theadvancement of the disease condition. In addition, factors associatedwith the particular subject being treated, including subject age,weight, diet and time of administration, will result in the need toadjust the dose to an appropriate therapeutic level. Advantageously,compounds of the present invention may be administered in a single dailydose or the total daily dosage may be administered in divided doses oftwo, three or four times daily.

Representative IUPAC names for the compounds of the present inventionwere derived using the ACD/LABS SOFTWARE™ Index Name Pro Version 4.5nomenclature software program provided by Advanced ChemistryDevelopment, Inc., Toronto, Ontario, Canada.

Abbreviations used in the instant specification, particularly theSchemes and Examples, are as follows:

Boc=tert-butoxycarbonylBuLi=n-butyllithiumCpd=compoundDCC=dicyclohexylcarbodiimideh=hour/hoursHOBT=hydroxybenzotriazoleKH=potassium hydrideMel=methyliodideNT=not testedrt/RT=room temperatureTFA=trifluoroacetic acidTMSBr=bromotrimethylsilane

General Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated more particularly in the scheme that follows. Since thescheme is an illustration, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art.

Scheme A

Scheme A is illustrative of a general method for the preparation ofcompounds of the invention by addition of a phosphonate or phosphinateanion, prepared from a phosphonate or phosphinate Compound A2, and anorganometallic base such as n-butyllithium, to an anhydride Compound A1in a solvent such as THF to afford a ketophosphonate or ketophosphinateCompound A3, wherein Z is hydrogen, Y is not present and X is one oxygensubstituent attached by a double-bond to the carbon in the position β toR₄.

Other compounds of the present invention may be obtained from CompoundA3 using standard ketone manipulations wherein the β position carbon maybe reduced from the ketone to a compound of Formula (I) wherein X and Yare both present or wherein Z is a bond. Examples of ketonemanipulations include, but are not limited to, the use of 1)organometallic reagents to form alkoxy groups; 2) hydroxylamines to formimino groups; and, 3) Lawesson's reagent to substitute a thio group inplace of the ketone (with appropriate protecting groups added to theCOOH group shown).

Compound A2, wherein R₆ is as previously defined, can be made accordingto known methods, such as those described in Katritsky, et. al., Org.Prep. Proced. Int., 1990, 22(2), 209-213; J. Am. Chem. Soc., 2002, 124,9386-9387; and, Chem. Ber., 1963, 96, 3184-3194. In an embodiment of ageneral synthetic method, the R₅ substitutent of Compound A4 is hydrogenand the R₆ substitutent is ethoxy.

Compound A2, wherein R₄ is heteroaryl, can be prepared from commerciallyavailable or known haloalkyl substituted heteroaryl starting materials(such as 3-bromomethyl-5-Cl-benzothiophene used to prepare Cpd 33) usingtechniques known to those skilled in the art.

Compound A3 may be coupled to the R₁ portion of Formula (I) usingstandard coupling reactions. For example, when R₁ is a secondary aminein a heterocyclyl ring, the nitrogen on the ring may be coupled toCompound A3 (similar to the reaction shown in Scheme A, e.g. the ringnitrogen in Compound A4 would be coupled with Compound A8). Appropriateblocking groups can be employed to minimize undesirable side reactions.Analogous coupling reactions with Compound A3 can be performed when R₁is N(R₇R₈) to couple the substituted amine to the carboxylic acid ofCompound A3. In one embodiment of the present invention the couplingreaction of Compound A3 with R₁ when R₁ is N(R₇R₈) and R₈ is aheterocycle is provided to further illustrate the present invention.

In Scheme A, the reaction of a suitably protected amino substitutedheterocycle Compound A4 (wherein the protected amino is substituted witha hydrogen atom for R₇ and an unsubstituted ad). heterocycle for R₈)with a Q-substituted R_(8a) Compound A5 (wherein Q is a suitable leavinggroup (such as, but not limited to, a halogen atom) and R_(8a) is asubstituent as previously defined in the R₈ ba).-bl) list) in a solventsuch as DMF containing a base (such as, but not limited to,triethylamine) provided an R_(8b) substituted Compound A6.

In an embodiment of a general synthetic method, the heterocyclyl portionof Compound A4 was further substituted on a nitrogen ring atom byreaction with an acid chloride Compound A5, wherein the Q portion waschlorine and wherein the R_(8a) portion was bc). carbonyl substitutedwith an R_(8b) substituent selected from C₁₋₈alkyl, aryl,aryl(C₁₋₈)alkyl, aryl(C₂₋₈)alkenyl, heteroaryl, heteroaryl(C₁₋₈)alkyl orheteroaryl(C₂₋₈)alkenyl. In an alternate embodiment, the reaction mayperformed by reaction with an acid chloride Compound A5, wherein the Qportion is chlorine and wherein the R_(8a) portion is bl). sulfonylsubstituted with an R_(8b) substituent; wherein R_(8b) is as previouslydefined.

Treatment of Compound A6 with a base such as potassium hydride followedby treatment with an R₇X alkylating agent such as iodomethane in asolvent such as THF yielded Compound A7. The amine Compound A8 can beobtained from Compound A7 by removal of the Boc protecting group upontreatment with an acid such as TFA in a solvent such as CH₂Cl₂. The freebase of Compound A8 is obtained upon treatment with a base such asaqueous Na₂CO₃.

Compound A9 can be prepared by a standard coupling procedure betweenCompound A3 and Compound A8 using routine reagents such as DCC and HOBTin a solvent such as CH₃CN. Dealkylation of Compound A9 with reagentsuch as bromotrimethylsilane in a solvent such as pyridine, followed bytreatment with dilute HCl afforded Compound A10 (wherein, in anembodiment of a general synthetic method, the R₅ ethyl group and the R₆ethoxy group were replaced with hydrogen). A salt of Compound A10 suchas target Compound A11 can be prepared by treating Compound A10 with amonobasic or dibasic amine such as tris(hydroxymethyl)aminomethane in asolvent system such as i-PrOH and water.

Scheme B

Scheme B is illustrative of an alternative general synthetic method forthe preparation of compounds of the invention by addition of a CompoundA2 (in an embodiment of an alternative general method, the R₅substitutent of Compound A2 is ethyl and the R₆ substitutent is ethoxy)and R″M (wherein R″M represents an organometallic reagent such as LiHMDS(lithium hexamethyldisilylazide), lithium tetramethylpiperidide orNaHMDS (sodium hexamethyldisilazide)) to an anhydride Compound A1.

The reaction is subsequently quenched with 6N HCl to a pH between 4 and6 to afford an enol Compound B1, wherein for a compound of Formula (I),Z is a bond, Y is not present and X is one oxygen substituent attachedby a single-bond to the carbon in the position β to R₄. Other compoundsof the present invention may be obtained from Compound B1 using standardketone manipulation wherein the enol double bond may be reduced to theketone; wherein for a compound of Formula (I), Y is not present and X isone oxygen substituent attached by a double-bond on the β positioncarbon. A coupling reagent (such as, but not limited to, chloroformates(such as, but not limited to, isobutyl chloroformate), cyanuricchloride, methanesulfonyl chloride, or diethyl chlorophosphate) may thenbe employed for ring closure to form a substituted lactone intermediateCompound B2 in the presence of a base such as, but not limited to, Et₃N.

Reaction of a dihydroxy substituted heterocycle Compound B3 (or otherketones and other protected ketones) with a Q-substituted R_(8a)Compound A5 in a solvent (such as, but not limited to, CH₂Cl₂, THF ormixtures thereof) containing a base (such as, but not limited to, sodiumbicarbonate, potassium carbonate) provided an R_(8b) substitutedCompound B4.

Compound B4 was treated with R₇NH₂ in a solvent (such as, but notlimited to, CH₂Cl₂, THF or mixtures thereof) then subjected to reductiveamination or hydrogenation using a hydride reducing agent (such as, butnot limited to, NaBH(OAc)₃, or hydrogenation with Pd, Pt or Nicatalyst). The free base of Compound A8 was obtained upon quenching thereaction with a base such as aqueous Na₂CO₃.

Compound A9 (in tautomeric equilibrium with Compound B6) was prepared byopening the 5-membered lactone ring intermediate Compound B2 withCompound A8 (or Compound B5, a salt of Compound A8) in the presence ofDIEA (diisopropylethylamine) in a solvent (such as, but not limited to,acetone or MEK (methylethyl ketone)).

Dealkylation of the equilibrium mixture of Compound A9-Compound B6 witha reagent (such as, but not limited to, TMSBr (bromotrimethylsilane) orTMSI) in a solvent (such as, but not limited to, CH₃CN or pyridine),followed by recrystallization afforded Compound A10 (wherein the R₅ethyl group is replaced with hydrogen and the R₆ ethoxy group isreplaced with hydroxy). A salt of Compound A10 such as Compound A11 (andtautomers thereof) was prepared by treating Compound A10 with a diaminesuch as tris(hydroxymethyl)aminomethane in a solvent system such as amixture of EtOH and water.

Scheme C

Scheme C is illustrative of an alternative method for the preparation ofthe intermediate Compound B2, wherein the enol Compound B1 is protonatedto the free acid ketone Compound A3 by adjusting the pH to about pH 1,followed by intramolecular dehydration to provide the target lactoneintermediate Compound B2.

Scheme D

Scheme D is illustrative of a method for the preparation of an acidaddition compound B5, wherein Compound A8 is reacted with an acid HA(such as, but not limited to, HCl, HBr or p-toluenesulfonic acid) toprovide the target Compound B5 which may be carried forward in place ofCompound A8 in the reaction with Compound B2.

Scheme E

Scheme E is illustrative of a method of the preparation of compounds ofFormula (II).

Compound A3 may be reacted with a compound of E1 under appropriateconditions to couple the compounds via an amide linkage. For example asalt can be formed from E1 and reacted with A3 to form an ammonium saltof the carboxylic acid that can be dehydrated to form the amide linkage.

Compound E1 can be prepared from commercially available or knownstarting materials using techniques known to those of skill in the art.

SPECIFIC SYNTHETIC EXAMPLES

Specific compounds which are representative of this invention wereprepared as per the following examples and reaction sequences; theexamples and the diagrams depicting the reaction sequences are offeredby way of illustration, to aid in the understanding of the invention andshould not be construed to limit in any way the invention set forth inthe claims which follow thereafter. The depicted intermediates may alsobe used in subsequent examples to produce additional compounds of thepresent invention. These reactions can be further optimized to increasethe yields. One skilled in the art would know how to increase suchyields through routine variations in reaction times, temperatures,solvents and/or reagents.

All chemicals were obtained from commercial suppliers and used withoutfurther purification. ¹H and ¹³C NMR spectra were recorded on a BrukerAC 300B (300 MHz proton) or a Bruker AM-400 (400 MHz proton)spectrometer with Me₄Si as an internal standard (s=singlet, d=doublet,t=triplet, br=broad). APCI-MS and ES-MS were recorded on a VG PlatformII mass spectrometer.

Example 1[2-[3-[[methyl[1-(2-naphthalenylcarbonyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonicAcid (Compound 2)

To a solution of 2.5M n-BuLi in hexanes (40 mL, 0.1 mol) in 70 mL of THFat −78° C. was added dropwise a solution of 1-naphthyldiethylphosphonate(Compound 1A, 28 g, 0.1 mol) in 60 mL THF over 30 min. After stirringfor an additional 30 min, 2,3-naphthalenedicarboxylic anhydride(Compound 1B, 20 g, 0.1 mol) was added portionwise via solid-additionfunnel to the mixture over 20 min. After the addition was complete, theslurry was allowed to reach 0° C. gradually where it was held foranother 1.5 h. Excess NH₄Cl (sat'd., aq.) was added, and the mixture wasfiltered through a pad of Celite 545. The filtrate was extracted with200 mL of EtOAc and the layers were separated. The organic phase wasconcentrated (without drying) under reduced pressure at rt and theresidue was triturated 4× with boiling ether. The residue was treatedwith 200 mL of EtOAc and adjusted to pH 3 with 2N HCl (aq.) withvigorous stirring. The layers were separated, and the organic phase waswashed once with H₂O, dried (Na₂SO₄) and concentrated to afford 24 g ofCompound 1C as a white powder: MS (ES) MH+=477; HPLC: 3.68 min.

To a solution of Compound 1D (4 g, 20 mmol) containing 3.1 mL oftriethylamine (22 mmol) in 45 mL of DMF was added Compound 1E (3.8 g, 20mmol). After stirring overnight, the mixture was filtered andconcentrated under reduced pressure. The residue was taken up in CH₂Cl₂and washed sequentially with H₂O, Na₂CO₃ (10%, aq.), H₂O, KHSO₄ (1N aq.)and H₂O. The organic phase was dried (Na₂SO₄), and concentrated toafford 6.0 g of Compound 1F as a foam: MS (ES) MH⁺=355.

Potassium hydride (2.3 g of a 35% oil dispersion; 20 mmol) was washedwith hexanes, then treated with 30 mL of THF and cooled to 0° C. To thesuspension was added dropwise a solution of Compound IF (5.9 g, 16.8mmol) in 15 mL of THF. The mixture was stirred at 0° C. for 0.5 h, thenstirred an additional 0.5 h at rt. The mixture was cooled to 0° C. andiodomethane (15.7 g, 100 mmol) was added dropwise. The mixture wasstirred at 0° C. for 0.5 h then warmed to rt and stirred an additional1.5 h. Excess 10% Na₂CO₃ (aq) was added slowly at 0° C., and thevolatiles were removed under reduced pressure. The aqueous layer wasextracted 3 times with EtOAc and the combined extracts were dried(Na₂SO₄) and concentrated to yield 6.1 g of Compound 1G as foam. HPLCR_(t)=3.76 min, 100%; MS (ES) MH+=369.

A solution of Compound 1G (6.1 g, 16.5 mmol) was dissolved in 15 mL of a1:1 solution of TFA:CH₂Cl₂ and stirred for 1 h at rt. Volatiles wereremoved under reduced pressure, and the residue was dissolved in CH₂Cl₂and treated with excess 10% Na₂CO₃ (aq). The layers were separated, andthe aqueous phase was extracted 3 times with CH₂Cl₂. The organicextracts were combined, dried (Na₂SO₄) and concentrated to afford 4.3 gof Compound 1H as a viscous oil. HPLC R_(t)=1.5 min, 100%; MS (ES)MH⁺=269.

A solution of Compound 1C (4.9 g, 10.3 mmol), Compound 1H (3.3 g, 12.3mmol) and HOBT (2.1 g, 15.4 mmol) in 100 mL CH₃CN was treated with asolution of DCC (2.5 g, 12.3 mmol) in 7 mL of CH₃CN. After stirring for12 h, 5 mL of DIPEA was added and the reaction was stirred for anadditional 48 h. The mixture was filtered and concentrated. The residuewas purified by flash column chromatography (silica: CH₂Cl₂:MeOH rampedfrom 98:1 to 95:5) to yield 6.9 g of Compound 1I. HPLC R_(t)=4.3 min; MS(ES) MH⁺=727.

To a solution of Compound 1I in 15 mL of pyridine was added 5 mL ofbromotrimethylsilane. The mixture was stirred for 15 min, thenconcentrated under reduced pressure. The residue was treated with excess3N HCl(aq), then stirred for 3 h. The white precipitate was collectedand rinsed with water, then triturated with CH₃CN to afford 5.1 g ofCompound 1J. HPLC R_(t)=3.6 min; MS (ES) MH+=671. To a solution ofCompound 1J in 50 mL of CH₃CN was added a solution oftris(hydroxymethyl)aminomethane (0.9 g, 7.7 mmol) in 7 mL of H₂O. Thesolution was filtered and the filtrate lyophilized after partialconcentration to remove most of the CH₃CN. The resulting white solid wasrecrystallized from i-PrOH to yield 5.5 g of Compound 2 as an off-whitesolid. HPLC: R_(t)=3.6 min; 100%; MS (ES) MH+=671; Anal. Calc'd forC₄₀H₃₅N₂O₆P.1.0 C₄H₁₁NO₃.1.0 i-PrOH-1.5H₂O: C, 64.23; H, 6.54; N, 4.79;H₂O, 3.08. Found: C, 63.93; H, 6.40; N, 4.85; H₂O, 2.74.

For Example 1, TLC was performed using Whatman 250-μm silica gel plates.Preparative TLC was performed with Analtech 1000-μm silica gel GFplates. Flash column chromatography was conducted with flash columnsilica gel (40-63 μm) and column chromatography was conducted withstandard silica gel. HPLC separations were carried out on three WatersPrepPak® Cartridges (25×100 mm, Bondapak® C18, 15-20 μm, 125 Å)connected in series; detection was at 254 nm on a Waters 486 UVdetector. Analytical HPLC was carried out on a Supelcosil ABZ+PLUScolumn (5 cm×2.1 mm), with detection at 254 nm on a Hewlett Packard 1100UV detector. Microanalysis was performed by Robertson MicrolitLaboratories, Inc.

Following the procedure of Example 1 and substituting the appropriatestarting materials, compounds and reagents, the following Compounds 1and 3-33 of the invention were also prepared:

MS m/e Cpd Name (MH⁺).  (1)[2-[3-[[methyl(4-phenylcyclohexyl)amino]carbonyl]-2- 592naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid  (3)[2-[3-[[[1-[(6-methoxy-2-naphthalenyl)carbonyl]-3- 687pyrrolidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid  (4)[2-[3-[[[1-[(6-bromo-2-naphthalenyl)carbonyl]-4- 771piperidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1- (M^(+Na))naphthalenyl)-2-oxoethyl]-phosphonic acid  (5)[2-[3-[[[1-[(2E)-3-(4-fluorophenyl)-1-oxo-2-propenyl]-3- 651pyrrolidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid  (6)[2-[3-[[methyl[1-[(2E)-1-oxo-3-phenyl-2-propenyl]-4- 647piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid  (7)[1-(1-naphthalenyl)-2-oxo-2-[3-[(4-phenyl-1- 564piperidinyl)carbonyl]-2-naphthalenyl]ethyl]-phosphonic acid  (8)[1-(1-naphthalenyl)-2-oxo-2-[3-[(4-oxo-1-phenyl-1,3,8- 634triazaspiro[4.5]dec-8-yl)carbonyl]-2-naphthalenyl]ethyl]- phosphonicacid  (9) [2-[3-[[methyl[1-[(2E)-3-(4-methylphenyl)-1-oxo-2-propenyl]-661 4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (10)[2-[3-[[methyl[1-[(2E)-1-oxo-3-[4-(trifluoromethyl)phenyl]-2- 715propenyl]-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (11)[2-[3-[[methyl[1-(2-naphthalenylcarbonyl)-4- 621piperidinyl]amino]carbonyl]-2-naphthalenyl]-2-oxo-1-phenylethyl]-phosphonic acid (12)[2-[3-[[4-(4-methoxyphenyl)-1-piperidinyl]carbonyl]-2- 594naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (13)[2-[3-[[[1-[(2E)-3-[4-(dimethylamino)phenyl]-1-oxo-2- 690propenyl]-4-piperidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (14)[2-[3-[[4-(3-methoxyphenyl)-1-piperidinyl]carbonyl]-2- 594naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (15)[2-[3-[[(1-benzoyl-4-piperidinyl)methylamino]carbonyl]-2- 621naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (16)[2-[3-[[4-(2-benzothiazolyl)-1-piperidinyl]carbonyl]-2- 621naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (17)[2-[3-[(cyclohexylmethylamino)carbonyl]-2-naphthalenyl]-1- 516(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (18)[2-[3-[[methyl[1-[1-oxo-3-[4-(trifluoromethyl)phenyl]propyl]-4- 717piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (19)[1-(1-naphthalenyl)-2-oxo-2-[3-[(3-phenyl-1- 550pyrrolidinyl)carbonyl]-2-naphthalenyl]ethyl]-phosphonic acid (20)[2-[3-[[methyl[1-(2-methyl-1-oxopropyl)-4- 587piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (21)[2-[3-[(cyclopentylmethylamino)carbonyl]-2-naphthalenyl]-1- 502(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (22) [2-[3-[[[4-(1,1- 572dimethylethyl)cyclohexyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (23)[2-[3-[[methyl[1-(2-naphthalenylcarbonyl)-4- 685piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid methyl ester (24)[2-[3-[[[1-[(6-hydroxy-2-naphthalenyl)carbonyl]-4- 687piperidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (25)[1-(1-naphthalenyl)-2-oxo-2-[3-[[3-(2-phenylethyl)-1- 578pyrrolidinyl]carbonyl]-2-naphthalenyl]ethyl]-phosphonic acid (26)[2-[3-[[(1-acetyl-4-piperidinyl)methylamino]carbonyl]-2- 559naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (27)[2-[3-[[methyl(4-methylcyclohexyl)amino]carbonyl]-2- 530naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (28)[2-[1-[[methyl(tricyclo[3.3.1.1^(3,7)]dec-1- 582ylmethyl)amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (29)[2-[3-[[methyl(4-phenyl-3-cyclohexen-1-yl)amino]carbonyl]-2- 590naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (30)[1-(1-naphthalenyl)-2-[3-[[[1-(2-naphthalenylcarbonyl)-4- 657piperidinyl]amino]carbonyl]-2-naphthalenyl]-2-oxoethyl]- phosphonic acid(31) [2-[2-[[methyl[1-(2-naphthalenylcarbonyl)-4- 621piperidinyl]amino]carbonyl]phenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (32)methyl[2-[3-[[methyl[1-(2-naphthalenylcarbonyl)-4- 669piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphinic acid (33)[1-(5-chlorobenzo[b]thien-3-yl)-2-[3-[[methyl[1-(2- 712naphthalenylcarbonyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-2-oxoethyl]-phosphonic acid

Example 2 Alternative Method of Synthesis for Compound 2

THF (tetrahydrofuran) (1081.0 mL) and 1-naphthyldiethylphosphonateCompound 2B (223.0 gm, 0.7612 mol) were combined in a flask and cooledto about −20° C. using a dry ice-methanol cooling bath. A solution of 1MLiHMDS (1597.0 mL, 1.597 mol) in THF was added to the cooled mixturewhile keeping the temperature at about −20° C. to form a fine slurrywhich was stirred for an additional 30 minutes. A2,3-naphthalinedicarboxylic anhydride Compound 2A (158.80 gm, 0.7612mol) was added portionwise over about a 1 h period while keeping thetemperature of the mixture at about −20° C. The addition funnel andflask walls were rinsed with THF (100.0 mL), the cooling bath wasremoved and the mixture temperature raised to about 5° C. for about 1.5h. Once the reaction was complete (as shown by HPLC), the final pH ofthe mixture was adjusted to about pH 5 by slowly adding 6N HCl (422 mL,2.34 mol) while the temperature of the mixture was maintained at about5° C. The mixture was stirred for about 30 min more at about 5° C. toprovide a crude product as a fine white solid. The crude product wasfiltered using a porcelain filter. The wet solid was then washed withwater (1000.0 mL), left to filter overnight, then dried at 70° C. toprovide a dilithium salt Compound 2C (365.1 gms; mass yield: 100.6%).Compound 2C was used in the next step without further purification.

Methanol (2500.0 mL) and water (360.0 mL) were added to a flask andstirred. Compound 2C (365.1 gm, 0.7612 mol) was added to the stirringsolution and the flask was rinsed with methanol (100.0 mL) to form aslurry. The slurry was stirred at RT for 30 minutes and then 12 N HCl(80.0 mL, 0.960 mol) was added over a 2 min period as the slurry turnedinto a hazy solution. The solution was stirred at RT untilcrystallization began, then was cooled to about 5° C. for 1 h to providea crude product as a white granular solid. The product was filtered andwashed with water (500.0 mL), then dried in vacuo overnight at atemperature of about 50° C. to provide Compound 2D (280 gms; mass yield:77.3%).

Compound 2D (199.8 gm) and THF (2 L) were combined in a flask, thenagitated and cooled to a temperature of from about 0° C. to about 5° C.NMM (4-methylmorpholine) (51.5 mL) was added to the flask while themixture temperature was maintained at a temperature of from about 0° C.to about 5° C. The mixture was then agitated for an additional 15 min oruntil a solution was obtained. IBCF (isobutylchloroformate) (56 mL) wasadded portionwise while the mixture temperature was maintained at atemperature of from about 0° C. to about 15° C. When the addition wascomplete, the mixture temperature was warmed to a temperature of fromabout 20° C. to about 25° C., then agitated for 1 h. Once the reactionwas complete, the NMM salts were filtered, washed with THF (150 mL) andallowed to dry. The filtrate was then combined with n-heptane (2.5 L)over a period of about 10 min and then agitated at a temperature of fromabout 20° C. to about 25° C. for about 30-45 min. Additional n-heptane(1.5 L) was added over a period of about 10 min. The mixture was thencooled to a temperature of from about 0° C. to about 5° C. and aged forabout 1.5 h. The resulting suspension was filtered and washed withn-heptane (250 mL), allowed to air dry over a period of about 30 min andthen dried in vacuo overnight at a temperature of from about 45 to about50° C. to provide Compound 2E (165 gms; mass yield: 88.4%).

DCM (dichloromethane) (600 mL) and a 2-naphthoyl chloride Compound 2F(189.0 gm) were combined in a flask and agitated until solubilized.4-Piperidone hydrate hydrochloride Compound 2G (150 g) and NaHCO₃(sodium hydrogen carbonate) (260.0 gms) were then added via additionfunnel. DCM (300 mL) was used to rinse the funnel and the resultingmixture was agitated for 18 h. Once the reaction was complete (as shownby HPLC), water (2.6 L) was added to the flask and the mixture wasstirred vigorously to dissolve the NaHCO₃. After a period of about 5 toabout 10 minutes, the layers were allowed to separate over a period ofabout 30 minutes. The aqueous layer was removed. Saturated aqueousNaHCO₃ (300 mL) was again added and the mixture agitated for a period ofabout 5 to about 10 min. The layers were allowed to separate over aperiod of about 30 min and the aqueous layer was removed. Water (300 mL)was added and the mixture stirred gently for a period of from about 5 toabout 10 min. The layers were allowed to separate over a period of about30 min and the organic layer (˜960 mL) containing Compound 2H wasremoved (concentration of Compound 2H in DCM: 235.98 mg/mL; calculatedmass of Compound 2H in DCM: 226.54 gms; calculated mass yield: 93.46%).

Compound 2H (˜50 gms, ˜265 mg/mL in DCM) and acetic acid (4.9 mL) werecombined in a flask and the mixture was cooled to a temperature of fromabout 0° C. to about 5° C. 2.0M MeNH₂ (methylamine) (296 mL) in THF wasadded portionwise while maintaining the mixture at a temperature of fromabout 0° C. to about 19° C. The mixture was allowed to warm to ambienttemperature and was agitated for a period of about 30 min. NaBH(OAc)₃(sodium triacetoxyborohydride) (51.4 gms) was then added portionwisewhile maintaining the solution at a temperature of from about 19° C. toabout 27° C. The mixture was aged for about 40 min at a temperature offrom about ambient to about 27° C. Once the reaction was complete (asshown by HPLC), water (500 mL) was added while maintaining the solutionat a temperature of below about 30° C. Sodium hydroxide (115 mL; 5% w/vin water) was then added to the mixture to raise the pH to from about pH10 to about pH 11. The mixture was agitated vigorously for a period offrom about 3 to about 10 min. The layers were separated and the aqueouslayer was removed. Water (143 mL) was added and the mixture agitated fora period of from about 3 to about 10 min. The layers were againseparated and the organic layer containing Compound 2I was removed(concentration of Compound 2I in DCM: 0.229 mg/mL; calculated mass ofCompound 2I in DCM: 45.18 gms; mass yield: 85.3%).

Compound 2I (150 mL, 0.069 mol) was placed in solution with CH₂Cl₂:THF(150 mL; 1:8) and concentrated to a thick oil in vacuo while maintainingthe mixture at a temperature of about or below 40° C. using a coolingbath. 2-Butanone (320 mL) was added portionwise to the thick oil totransfer the oil to another flask. The mixture was agitated andEtN(i-Pr)₂ (diisopropylethylamine) (11.0 mL, 0.063 mol) and Compound 2E(27.3 gms, 0.057 mol) were added. The mixture was heated to atemperature of about 65° C. for a period of from about 6 to about 7 h.Once the reaction was complete (as shown by HPLC), the mixture wascooled to ambient temperature and crystallized over a period of fromabout 72 to about 96 h (the product can take up to 48 h to start tocrystallizing, having a cloud point time around 28 h). The product wasfiltered and washed with acetone (2×10 mL) (each wash), then dried invacuo overnight at a temperature of about 75° C. to provide Compound 2J(31.4 gms; yield: 75.1%) as a white powder.

Compound 2J (10.0 g) and acetonitrile (40 mL) under nitrogen were addedto a flask to form a suspension. The suspension was agitated for aperiod of from about 5 to about 10 min, then bromotrimethylsilane (10mL) was added via additional funnel over a period of from about 10 toabout 15 min at RT. The solution was stirred for at least a time periodof about 1 h at rt. Once the reaction was complete (as shown by HPLC),the mixture was transferred to an addition funnel and then added towater (250 mL). The resulting slurry was stirred vigorously during theaddition and the temperature maintained at from about 20° C. to about25° C. The slurry was further agitated over a period of from about 1 toabout 1.5 h, then filtered and washed with water (2×15 mL). Theresulting wet cake was then dried in vacuo overnight at a temperature ofabout 40° C. to provide a crude product Compound 2K (10.2 gms) as awhite solid.

Compound 2K (110.0 gms, 0.127 mol) and methanol (550 mL) were added to aflask to form a slurry. The slurry was stirred at RT over a period offrom about 55 to about 60 min (the recrystallization mixture gave a hazysolution within about 5 minutes after adding MeOH and gradually affordeda white suspension after about 30 minutes). An acetone:water (1100 mL;4:1) solution was added and the suspension was stirred at RT for aperiod of from about 180 to about 190 min to afford a white solid. Thesolid was filtered and washed with water (3×350 mL), forming a wet cakewas then dried in vacuo overnight at a temperature of from about 30 toabout 35° C. to provide a recrystallized Compound 2K (82.3 gms; yield:96.1%) as a fine white solid.

Recrystallized Compound 2K (30.0 g, 0.0431 mol) andtris(hydroxymethyl)aminomethane (13.07 g, 0.107 mol; a clear whitecrystalline solid) were combined in a flask and ethanol (300 mL) andwater (30 mL) were added. The solution was agitated to provide a clearsolution after a period of about 15 min. A thin suspension was formedafter a period of from about 2 to about 3 h and a thick white suspensionwas formed after a period of from about 3 to about 5 h (the mixture mayneed to be seeded to enhance crystallization if a thin suspension is notformed after a period of about 3 h). The suspension was stirred at RTfor an additional period of about 4 h. The thick suspension was thinnedby adding ethanol (180 mL), then filtered and washed with ethanol (120mL), allowed to air dry over a period of about 30 min and then dried invacuo for a time period of from about 24 to about 67 h at a temperatureof about 40° C. to provide Compound 2E (38.6 gms; yield: 91.8%) as abis-tromethane salt (ratio of tris(hydroxymethyl)aminomethane: Compound2E: 1.99:1).

For Example 2, analytical HPLC was carried out using Phenomenex Luna (15cm×4.6 mm; 5μ; detection was at 220 nm), Phenomenex Luna 5μ C18(2) (4.6mm×250; detection was at 225 nm) and Synergi 4μ MAX-RP 80A (15 cm×4.6mm; detection was at 225 nm) columns. Microanalysis was performed byQuantitative Technologies, Inc.

Example 3

As a specific embodiment of an oral composition, 100 mg of the Compound2 of Example 1 is formulated with sufficient finely divided lactose toprovide a total amount of 580 to 590 mg to fill a size 0 hard gelcapsule.

Example 4

A solution of 4A (1.0 g, 2.1 mmol), 4-N-Boc-aminopiperidine (0.42 g, 2.2mmol; Astatech Inc.) and HOBt (0.28 g, 2.1 mmol) in 5 mL of DMF wastreated with a solution of DCC (0.43 g, 2.1 mmol) in 1 mL of DMFdropwise. After stirring for 24 h, the mixture was filtered throughdicalite and the filtrate concentrated under reduced pressure. Theresidue was purified by flash column chromatography (silica; 5%CH₃OH—CH₂Cl₂) to afford 1 g of 4B as a white foam, 72%. MS (ES) m/z 731(MH⁺ adduct ion with MeOH and CH₃CN).

A solution of 20% TFA in CH₂Cl₂ and 4B (1 g, 1.5 mmol) was stirred for45 min, then concentrated under a stream of N₂. The residue wastriturated with ether to give 0.80 g of C as a white powder (TFA salt):MS (ES) m/z=530 (M-C₂H₅)⁺.

To a mixture of 0.40 g (0.59 mmol) of 4C and 0.17 mL (1.2 mmol) of Et₃Nin 30 mL of CH₂Cl₂ was added a solution of 2-naphthoyl chloride (0.11 g,0.60 mmol) in 1 mL of CH₂Cl₂. The reaction was stirred for 2 h, thendiluted with water and the layers were separated. The organic layer waswashed sequentially with H₂O, NaHCO₃ (satd, aq.), 1N KHSO₄ (aq), andH₂O, then dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash column chromatography (silica, 5% CH₃OH—CH₂Cl₂) toafford 0.29 g (70%) of 4D as a white powder: MS (ES) m/z 713 (MH⁺).

A solution of 0.29 g (0.40 mmol) of 4D in 2.5 mL of pyridine was treatedwith 0.4 mL (3.3 mmol) of bromotrimethylsilane and the mixture wasstirred for 2 h. Volatiles were removed under reduced pressure, and thewhite solid residue was treated with 15 mL of 1N HCl (aq). The slurrywas stirred for 2.5 h and the white solid was collected and rinsed withH₂O. The solid was triturated with CH₃CN to yield 0.12 g of the titlecompound (46%) as a white powder: MS (ES) m/z 657 (MH⁺).

To a stirred solution of 5A (0.55 g, 1.16 mmol), the trifluoroacetatesalt of 5B (0.5 g, 1.16 mmol), triethylamine (1.28 mmol, 0.18 mL), andHOBt (0.24 g, 1.75 mmol) in 5 mL of acetonitrile was added a solution ofDCC in 2 mL of acetonitrile. (0.26 g, 1.28 mmol). The reaction wasstirred for 24 h, then treated with 1 mL of DIPEA, and stirred anadditional 5 h. The mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (silica; 100% CH₂Cl₂->98% CH₂Cl₂-MeOH) to afford0.66 g of 5C as a foam: MS (ES⁺) MH⁺=735.

To a stirred solution of 5C (0.11 g, 0.75 mmol) in 1 mL of pyridine wasadded 0.15 mL of bromotrimethylsilane. The reaction was stirred for 1.5h, then concentrated under reduced pressure. The residue was stirredwith excess 3N HCl for 1 h, and the product collected and washedsequentially with water and ether. The product was suspended inacetonitrile and stirred for 0.5 h at 0° C. then collected to afford0.067 g of the title compound as a white solid: MS (ES⁺) MH⁺=679.

Following the procedure of Example 5 and substituting the appropriatestarting materials, compounds and reagents, the following Compounds ofthe invention were also prepared:

MS m/e Cpd R₁₀ (MH⁺). 37 naphthalene-2-yl-acetyl 657 38 2-naphthoyl 641(MH⁻) 39 1-(4-hydroxyphenyl) 581 40 1-(4-methoxyphenyl) 595 41N-[5-(sulfonyl)-thiophene-2-ylmethyl]-benzamide 768 426-chloro-5-sulfonyl-imidazo[2,1-b]thiazole 709 43Naphthyl-2-aminocarbonyl 658 44 1-(4-fluorophenyl) 583

BIOLOGICAL EXPERIMENTAL EXAMPLES

The utility of the compounds of the present invention as a serineprotease inhibitor and, particularly, as a cathepsin G or chymaseinhibitor useful for the treatment of inflammatory or serine proteasemediated disorders can be determined according to the proceduresdescribed herein.

Example 1 Enzyme-Catalyzed Hydrolysis Assays Cathepsin G

Enzyme-catalyzed hydrolysis rates were measured spectrophotometricallyusing human neutrophil cathepsin G (Athens Research and Technology) orhuman skin chymase (Cortex Biochem), a chromogenic substrate(Suc-Ala-Ala-Pro-Phe-pNa) (Bachem) in aqueous buffer (100 mM Hepes, 500mM NaCl, pH 7.4 for catG; 450 mM Tris, 1800 mM NaCl, pH 8.0 forchymase), and a microplate reader (Molecular Devices). IC₅₀ experimentswere conducted by fixing the enzyme and substrate concentrations (70 nMenzyme, 5 mM substrate for cat G, 10 nM enzyme, 0.7 mM substrate forchymase) and varying the inhibitor concentration. Changes in absorbanceat 405 nM were monitored using the software program Softmax (MolecularDevices), upon addition of enzyme, with and without inhibitor present at37° C. for 30 minutes. Percent inhibition was calculated by comparingthe initial reaction slopes of the samples without inhibitor to thosewith inhibitor. IC₅₀ values were determined using a four parameter fitlogistics model. The term “NT” indicates a compound that was not tested.

Table 4 summarizes the assay results for cathepsin G and chymaseinhibition for compounds of the present invention:

TABLE 4 IC₅₀ (μM) IC₅₀ (μM) Cpd CatG n Chymase n 1 0.083 ± 0.014 70.0053 ± 0.0019 8 2 0.081 ± 0.009 70 0.0067 ± 0.0018 70 3 0.068 ± 0.0192 0.072 ± 0.008 3 4 0.090 ± 0.020 5 0.0039 ± 0.0001 4 5 0.072 ± 0.021 50.2 ± 0.4 6 6 0.067 ± 0.014 4 0.0035 ± 0.0015 2 7 0.210 ± 0.050 12 0.008± 0.022 1 8 0.130 ± 0.010 11 0.0074 ± 0.0022 8 9 0.053 ± 0.015 5 0.011 ±0.003 2 10 0.053 ± 0.016 5 0.014 ± 0.006 5 11 4.9 ± 2.8 2 0.032 1 120.179 ± 0.038 10 0.0073 ± 0.0017 10 13 0.064 ± 0.008 3 0.004 1 14 0.230± 0.030 6 0.010 ± 0.001 9 15 0.075 ± 0.030 5 0.017 ± 0.005 3 16 0.190 ±0.020 7 0.0085 ± 0.0023 7 17 0.098 ± 0.026 4 0.0072 ± 0.0015 6 18 0.028± 0.006 3  0.0010 1 19 0.238 ± 0.030 8 0.022 ± 0.062 9 20 0.090 ± 0.0235 0.004 ± 0.002 2 21 0.070 ± 0.020 5 0.0096 ± 0.0034 5 22 0.140 ± 0.04018 0.009 ± 0.023 12 23  0.670 1 0.416 1 24 0.078 ± 0.015 7 0.0035 ±0.0013 6 25 0.156 ± 0.028 7 0.0097 ± 0.0035 7 26 0.096 ± 0.018 3 0.015 ±0.001 3 27 0.070 ± 0.010 4 0.0051 ± 0.0022 4 28 0.400 ± 0.090 11 0.036 ±0.011 10 29 0.150 ± 0.030 13 0.0082 ± 0.0028 10 30 0.590 ± 0.040 20.0158 ± 0.0008 2 31 >100.0   1 14.95 ± 0.67  2 32 0.86 ± 0.03 2 0.31  133 0.121 ± 0.007 2 0.001 ± 0.000 2 34 0.09 ± 0.04 3 0.007 ± 0.001 2 350.56 ± 0.18 3 37 0.74 ± 0.29 3 38 0.78 ± 0.22 2 39 0.18 ± 0.05 2 40 0.17± 0.05 2 41 0.31 1 42 0.14 ± 0.03 2 43 0.95 ± 0.21 5 44 0.52 ± 0.29 2

Example 2 Anti-Asthmatic Effects in a Sheep Model of Asthma

The efficacy of Compound 2 for the treatment of asthma was evaluated ina validated model of Ascaris suum antigen-induced asthmatic response inconscious sheep (Abraham, W. M., Pharmacology of allergen-induced earlyand late airway responses and antigen-induced airway hyperresponsivenessin allergic sheep, Pulmonary Pharmacology, 1989, 2, 33-40).

Experimental Protocol

Baseline dose response curves to aerosol carbachol were obtained 1-3days prior to antigen challenge. Baseline values of specific lungresistance (SR_(L)) were obtained and the sheep were then given aspecified amount (mg) of the test compound as an inhaled aerosol at aspecified time before antigen challenge. Post drug measurements ofSR_(L) were obtained and the sheep were then challenged with Ascarissuum antigen. Measurements of SR_(L) were obtained immediately afterchallenge, hourly from 1-6 h after challenge and on the half-hour from6½-8 h after challenge. Measurements of SR_(L) were obtained 24 h afterchallenge followed by a 24 h post-challenge with carbachol to measureairway hyperreactivity.

Compound 2 was administered as an aerosol at 0.1 mg/Kg/dose, twice-a-day(BID) for three consecutive days, followed by a dose on day 4, 0.5 hprior to antigen challenge. Ascaris suum antigen challenge was given atthe zero time point.

FIG. 1 shows that the early airway response (0-2 h after antigenchallenge) was dramatically reduced and that the late airway response(6-8 h after antigen challenge) was completely blocked (n=4sheep/group).

FIG. 2 shows that the delayed airway hyperreactivity measured at 24 hpost antigen challenge as measured using carbachol challenge was alsocompletely blocked.

In addition to blocking the increase in airway resistance, as shown inTable 5, Compound 2 also blocked the rise in inflammatory cell numbersin the broncho-alveolar lavage (BAL) fluid sampled from these sheep.

TABLE 5 Treatment Group/Time BAL Cell Count (×1000/mL) BaselineNeutrophils Lymphocytes Eosinophils Macrophages Baseline 22.04 ± 12.894.82 ± 1.74 6.29 ± 3.98 172.2 ± 20.8 8 h Post Antigen 24.55 ± 14.0813.39 ± 5.44  61.58 ± 29.87 209.3 ± 44.7 24 h Post Antigen 111.7 ± 38.9 36.30 ± 15.68 168.4 ± 95.1  245.6 ± 20.4 Compound 2 (1.0 mg/kg × 4 days)(last dose - 30 min prior to antigen challenge) Baseline 12.66 ± 2.07 3.15 ± 0.79 0.00 69.06 ± 1.97 8 h Post Antigen 3.17 ± 0.65 4.16 ± 1.100.37 ± 0.32 77.85 ± 2.36 24 h Post Antigen 3.86 ± 0.95 3.72 ± 0.77 0.04± 0.03 75.16 ± 2.71

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A method for treating an inflammatory or serine protease mediateddisorder selected from the group consisting of pulmonary inflammatoryconditions, chronic obstructive pulmonary diseases, asthma, psoriasis,allergic rhinitis, viral rhinitis, ischemia, arthritis,glomerulonephritis, reperfusion injury, hypertension, and vascularrestenosis in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of a compound of Formula(IIa):

wherein R₁₀ is selected from the group consisting of: a) sulfonylsubstituted with a substituent selected from the group consisting ofC₁₋₈ alkyl, aryl, aryl(C₁₋₈)alkyl, aryl(C₂₋₈)alkenyl, cycloalkyl,cycloalkenyl, heterocycl, heteroaryl, heteroaryl(C₁₋₈)alkyl andheteroaryl(C₂₋₈)alkenyl; b) carbonyl substituted with a substituentselected from the group consisting of C₁₋₈ alkyl, aryl, aryl(C₁₋₈)alkyl,aryl(C₂₋₈)alkenyl, cycloalkyl, cycloalkenyl, heterocycl heteroaryl,heteroaryl(C₁₋₈)alkyl, heteroaryl(C₂₋₈)alkenyl, —OR¹¹ and amino (withtwo substituents independently selected from the group consisting ofhydrogen, C₁₋₈ alkyl, aryl, arylC₁₋₈ alkyl, arylcarbonyl, arylC₁₋₈ alkylcarbonyl and heteroaryl C₁₋₈ alkyl); c) C₁₋₈ alkyl optionallysubstituted on a terminal carbon atom with a substituent selected fromthe group consisting of aryl, cycloalkyl, cycloalkenyl, heterocycl,heteroaryl, (halo)₁₋₃, hydroxy, —C(O)R₁₂ and amino (with twosubstituents independently selected from the group consisting ofhydrogen, C₁₋₈ alkyl, arylC₁₋₈ alkyl, arylcarbonyl, arylC₁₋₈ alkylcarbonyl and heteroaryl C₁₋₈ alkyl); d) aryl; e) heteroaryl; f)cycloalkyl g) cycloalkenyl; and h) heterocyclyl wherein the heterocycl,cycloalkyl, cycloalkenyl portion of a), b), and c), the cylcoalkyl f),cylcoalkenyl g), and heterocyclyl h) are optionally substituted with oneto two substituents independently selected from the group consisting of:ea) oxo eb) carbonyl substituted with a substituent selected from thegroup consisting of C₁₋₈ alkyl, aryl, aryl(C₁₋₈)alkyl,aryl(C₂₋₈)alkenyl, cycloalkyl, cycloalkenyl, heterocycl heteroaryl,heteroaryl(C₁₋₈)alkyl, heteroaryl(C₂₋₈)alkenyl and amino (with twosubstituents independently selected from the group consisting ofhydrogen, C₁₋₈ alkyl, arylC₁₋₈ alkyl, arylcarbonyl, arylC₁₋₈ alkylcarbonyl and heteroaryl C₁₋₈ alkyl); ec) C₁₋₈ alkyl optionallysubstituted with a substituent selected from the group consisting ofamino (with two substituents independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, arylC₁₋₈ alkyl, arylcarbonyl,arylC₁₋₈ alkyl carbonyl and heteroaryl C₁₋₈ alkyl), aryl, cycloalkyl,cycloalkenyl, heterocycl, heteroaryl, (halo)₁₋₃, and hydroxy; ed) aryl;and ef) (halo)₁₋₃ wherein the aryl portion of the a), b), c), ec) anded) substituents, the heteroaryl portion of the a), b), c), and ec)substituents and the d) aryl and e) heteroaryl substituents areoptionally substituted with one to four substituents independentlyselected from the group consisting of fa) C₁₋₄ alkyl optionallysubstituted on a terminal carbon atom with a substituent selected fromthe group consisting of aryl, cycloalkyl, cycloalkenyl, heterocycl,heteroaryl, (halo)₁₋₃, hydroxy, —C(O)R₁₂ and amino (with twosubstituents independently selected from the group consisting ofhydrogen, C₁₋₈ alkyl, arylC₁₋₈ alkyl, arylcarbonyl, arylC₁₋₈ alkylcarbonyl and heteroaryl C₁₋₈ alkyl); fb) C₂₋₄ alkenyl optionallysubstituted on a terminal carbon atom with a substituent selected fromthe group consisting of amino (with two substituents independentlyselected from the group consisting of hydrogen and C₁₋₈ alkyl),(halo)₁₋₃ and hydroxy; fc) C₁₋₄ alkoxy optionally substituted on aterminal carbon atom with a substituent selected from the groupconsisting of (halo)₁₋₃ and hydroxy; fd) cycloalkyl, fe) heterocyclyl,ff) aryl optionally substituted with one to four substituentsindependently selected from the group consisting of C₁₋₈ alkyl andhalogen; fg) heteroaryl, fh) hydroxy; fi) hydroxy; fj) nitro; and fk)(halo)₁₋₃; wherein the aryl portion of the arylC₁₋₈ alkyl, arylcarbonyl,arylC₁₋₈ alkyl carbonyl of fa) are optionally substituted with one tofour substituents independently selected from the group consisting ofC₁₋₄ alkyl (optionally substituted on a terminal carbon atom with asubstituent selected from the group consisting of amino (substitutedwith two substituents independently selected from the group consistingof hydrogen and C₁₋₈ alkyl), (halo)₁₋₃ and hydroxy), C₁₋₄ alkoxy(optionally substituted on a terminal carbon atom with a substituentselected from the group consisting of (halo)₁₋₃), amino (substitutedwith two substituents independently selected from the group consistingof hydrogen and C₁₋₄ alkyl), halogen, hydroxy and nitro.
 2. The methodof claim 1 wherein the therapeutically effective amount is from about0.001 mg/kg/day to about 300 mg/kg/day.
 3. The method of treating aninflammatory or serine protease mediated disorder selected from thegroup consisting of pulmonary inflammatory conditions, chronicobstructive pulmonary diseases, asthma, psoriasis, allergic rhinitis,viral rhinitis, ischemia, arthritis, glomerulonephritis, reperfusioninjury, hypertension, and vascular restenosis in a subject in needthereof comprising administering to the subject from about 0.001mg/kg/day to about 300 mg/kg/day of the composition of claim
 1. 4. Themethod of claim 3 wherein said disorder is asthma.
 5. The method ofclaim 3 wherein said disorder is chronic obstructive pulmonary diseases.